the invention embraces compounds useful in treating or suppressing diseases , developmental delays and symptoms related to oxidative stress such as mitochondrial disorders , impaired energy processing disorders , neurodegenerative diseases and diseases of aging , and methods of using such compounds for treating or suppressing an oxidative stress disorder , or for modulating , normalizing , or enhancing one or more ( e . g . one , two , three , or more ) energy biomarkers . the abbreviations used herein have their conventional meaning within the chemical and biological arts , unless otherwise specified . reference to “ about ” a value or parameter herein includes ( and describes ) variations that are directed to that value or parameter per se . for example , description referring to “ about x ” includes description of “ x ”. the terms “ a ” or “ an ,” as used in herein means one or more , unless context clearly dictates otherwise . by “ subject ,” “ individual ,” or “ patient ” is meant an individual organism , preferably a vertebrate , more preferably a mammal , most preferably a human . “ treating ” a disorder with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein , with or without additional therapeutic agents , in order to reduce or eliminate either the disorder or one or more symptoms of the disorder , or to retard the progression of the disorder or of one or more symptoms of the disorder , or to reduce the severity of the disorder or of one or more symptoms of the disorder . “ suppression ” of a disorder with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein , with or without additional therapeutic agents , in order to suppress the clinical manifestation of the disorder , or to suppress the manifestation of adverse symptoms of the disorder . the distinction between treatment and suppression is that treatment occurs after adverse symptoms of the disorder are manifest in a subject , while suppression occurs before adverse symptoms of the disorder are manifest in a subject . suppression may be partial , substantially total , or total . because some of the disorders are inherited , genetic screening can be used to identify patients at risk of the disorder . the compounds and methods of the invention can then be administered to asymptomatic patients at risk of developing the clinical symptoms of the disorder , in order to suppress the appearance of any adverse symptoms . “ therapeutic use ” of the compounds discussed herein is defined as using one or more of the compounds discussed herein to treat or suppress a disorder , as defined above . an “ effective amount ” of a compound is an amount of the compound sufficient to modulate , normalize , or enhance one or more energy biomarkers ( where modulation , normalization , and enhancement are defined below ). a “ therapeutically effective amount ” of a compound is an amount of the compound , which , when administered to a subject , is sufficient to reduce or eliminate either a disorder or one or more symptoms of a disorder , or to retard the progression of a disorder or of one or more symptoms of a disorder , or to reduce the severity of a disorder or of one or more symptoms of a disorder , or to suppress the clinical manifestation of a disorder , or to suppress the manifestation of adverse symptoms of a disorder . a therapeutically effective amount can be given in one or more administrations . an “ effective amount ” of a compound embraces both a therapeutically effective amount , as well as an amount effective to modulate , normalize , or enhance one or more energy biomarkers in a subject . “ modulation ” of , or to “ modulate ,” an energy biomarker means to change the level of the energy biomarker towards a desired value , or to change the level of the energy biomarker in a desired direction ( e . g ., increase or decrease ). modulation can include , but is not limited to , normalization and enhancement as defined below . “ normalization ” of , or to “ normalize ,” an energy biomarker is defined as changing the level of the energy biomarker from a pathological value towards a normal value , where the normal value of the energy biomarker can be 1 ) the level of the energy biomarker in a healthy person or subject , or 2 ) a level of the energy biomarker that alleviates one or more undesirable symptoms in the person or subject . that is , to normalize an energy biomarker which is depressed in a disease state means to increase the level of the energy biomarker towards the normal ( healthy ) value or towards a value which alleviates an undesirable symptom ; to normalize an energy biomarker which is elevated in a disease state means to decrease the level of the energy biomarker towards the normal ( healthy ) value or towards a value which alleviates an undesirable symptom . “ enhancement ” of , or to “ enhance ,” energy biomarkers means to intentionally change the level of one or more energy biomarkers away from either the normal value , or the value before enhancement , in order to achieve a beneficial or desired effect . for example , in a situation where significant energy demands are placed on a subject , it may be desirable to increase the level of atp in that subject to a level above the normal level of atp in that subject . enhancement can also be of beneficial effect in a subject suffering from a disease or pathology such as e . g . a mitochondrial disorder , in that normalizing an energy biomarker may not achieve the optimum outcome for the subject ; in such cases , enhancement of one or more energy biomarkers can be beneficial , for example , higher - than - normal levels of atp , or lower - than - normal levels of lactic acid ( lactate ) can be beneficial to such a subject . by modulating , normalizing , or enhancing the energy biomarker coenzyme q is meant modulating , normalizing , or enhancing the variant or variants of coenzyme q which is predominant in the species of interest . for example , the variant of coenzyme q which predominates in humans is coenzyme q10 . if a species or subject has more than one variant of coenzyme q present in significant amounts ( i . e ., present in amounts which , when modulated , normalized , or enhanced , can have a beneficial effect on the species or subject ), modulating , normalizing , or enhancing coenzyme q can refer to modulating , normalizing or enhancing any or all variants of coenzyme q present in the species or subject . while the compounds described herein can occur and can be used as the neutral ( non - salt ) compound , the description is intended to embrace all salts of the compounds described herein , as well as methods of using such salts of the compounds . in one embodiment , the salts of the compounds comprise pharmaceutically acceptable salts . pharmaceutically acceptable salts are those salts which can be administered as drugs or pharmaceuticals to humans and / or animals and which , upon administration , retain at least some of the biological activity of the free compound ( neutral compound or non - salt compound ). the desired salt of a basic compound may be prepared by methods known to those of skill in the art by treating the compound with an acid . examples of inorganic acids include , but are not limited to , hydrochloric acid , hydrobromic acid , sulfuric acid , nitric acid , and phosphoric acid . examples of organic acids include , but are not limited to , formic acid , acetic acid , propionic acid , glycolic acid , pyruvic acid , oxalic acid , maleic acid , malonic acid , succinic acid , fumaric acid , tartaric acid , citric acid , benzoic acid , cinnamic acid , mandelic acid , sulfonic acids , and salicylic acid . salts of basic compounds with amino acids , such as aspartate salts and glutamate salts , can also be prepared . the desired salt of an acidic compound can be prepared by methods known to those of skill in the art by treating the compound with a base . examples of inorganic salts of acid compounds include , but are not limited to , alkali metal and alkaline earth salts , such as sodium salts , potassium salts , magnesium salts , and calcium salts ; ammonium salts ; and aluminum salts . examples of organic salts of acid compounds include , but are not limited to , procaine , dibenzylamine , n - ethylpiperidine , n , n - dibenzylethylenediamine , and triethylamine salts . salts of acidic compounds with amino acids , such as lysine salts , can also be prepared . the invention also includes , if chemically possible , all stereoisomers of the compounds , including diastereomers and enantiomers . the invention also includes mixtures of possible stereoisomers in any ratio , including , but not limited to , racemic mixtures . unless stereochemistry is explicitly indicated in a structure , the structure is intended to embrace all possible stereoisomers of the compound depicted . if stereochemistry is explicitly indicated for one portion or portions of a molecule , but not for another portion or portions of a molecule , the structure is intended to embrace all possible stereoisomers for the portion or portions where stereochemistry is not explicitly indicated . the compounds can be administered in prodrug form . prodrugs are derivatives of the compounds , which are themselves relatively inactive but which convert into the active compound when introduced into the subject in which they are used by a chemical or biological process in vivo , such as an enzymatic conversion . suitable prodrug formulations include , but are not limited to , peptide conjugates of the compounds of the invention and esters of compounds of the inventions . further discussion of suitable prodrugs is provided in h . bundgaard , design of prodrugs , new york : elsevier , 1985 ; in r . silverman , the organic chemistry of drug design and drug action , boston : elsevier , 2004 ; in r . l . juliano ( ed . ), biological approaches to the controlled delivery of drugs ( annals of the new york academy of sciences , v . 507 ), new york : new york academy of sciences , 1987 ; and in e . b . roche ( ed . ), design of biopharmaceutical properties through prodrugs and analogs ( symposium sponsored by medicinal chemistry section , apha academy of pharmaceutical sciences , november 1976 national meeting , orlando , fla . ), washington : the academy , 1977 . the description of compounds herein also includes all isotopologues , for example , partially deuterated or perdeuterated analogs of all compounds herein . “( c 1 - c 6 ) alkyl ” is intended to embrace a saturated linear , branched , or cyclic hydrocarbon , or any combination thereof , of 1 to 6 carbon atoms . non - limiting examples of “( c 1 - c 6 ) alkyl ” include methyl , ethyl , n - propyl , isopropyl , cyclopropyl , n - butyl , isobutyl , sec - butyl , t - butyl , cyclobutyl , cyclopropyl - methyl , methyl - cyclopropyl , pentyl , cyclopentyl , hexyl , and cyclohexyl . the point of attachment of the ( c 1 - c 6 ) alkyl group to the remainder of the molecule can be at any chemically possible location on the ( c 1 - c 6 ) alkyl group . “( c 1 - c 6 ) haloalkyl ” is intended to embrace any c 1 - c 6 alkyl substituent having at least one halogen substituent ( e . g . one , two , three , four , or greater than four halogen substituents , provided the number of halogen substituents is chemically possible ); the halogen can be attached via any valence on the c 1 - c 6 alkyl group . some examples of c 1 - c 6 haloalkyl are — cf 3 , — ccl 3 , — chf 2 , — chcl 2 , — chbr 2 , — ch 2 f , — ch 2 cl , or — cf 2 cf 3 . by “ respiratory chain disorder ” is meant a disorder which results in the decreased utilization of oxygen by a mitochondrion , cell , tissue , or individual , due to a defect or disorder in a protein or other component contained in the mitochondrial respiratory chain . by “ protein or other component contained in the mitochondrial respiratory chain ” is meant the components ( including , but not limited to , proteins , tetrapyrroles , and cytochromes ) comprising mitochondrial complex i , ii , iii , iv , and / or v . “ respiratory chain protein ” refers to the protein components of those complexes , and “ respiratory chain protein disorder ” is meant a disorder which results in the decreased utilization of oxygen by a mitochondrion , cell , tissue , or individual , due to a defect or disorder in a protein contained in the mitochondrial respiratory chain . the terms “ parkinson &# 39 ; s ”, ( also called “ parkinsonism ” and “ parkinsonian syndrome ”) (“ pd ”) is intended to include not only parkinson &# 39 ; s disease but also drug - induced parkinsonism and post - encephalitic parkinsonism . parkinson &# 39 ; s disease is also known as paralysis agitans or shaking palsy . it is characterized by tremor , muscular rigidity and loss of postural reflexes . the disease usually progresses slowly with intervals of 10 to 20 years elapsing before the symptoms cause incapacity . due to their mimicry of effects of parkinson &# 39 ; s disease , treatment of animals with methamphetamine or mptp has been used to generate models for parkinson &# 39 ; s disease . these animal models have been used to evaluate the efficacy of various therapies for parkinson &# 39 ; s disease . the term “ friedreich &# 39 ; s ataxia ” is intended to embrace other related ataxias , and is also sometimes referred to as hereditary ataxia , familial ataxia , or friedreich &# 39 ; s tabes . the term “ ataxia ” is an aspecific clinical manifestation implying dysfunction of parts of the nervous system that coordinate movement , such as the cerebellum . people with ataxia have problems with coordination because parts of the nervous system that control movement and balance are affected . ataxia may affect the fingers , hands , arms , legs , body , speech , and eye movements . the word ataxia is often used to describe a symptom of incoordination which can be associated with infections , injuries , other diseases , or degenerative changes in the central nervous system . ataxia is also used to denote a group of specific degenerative diseases of the nervous system called the hereditary and sporadic ataxias . ataxias are also often associated with hearing impairments . there are three types of ataxia , cerebellar ataxia , including vestibulo - cerebellar dysfunction , spino - cerebellar dysfunction , and cerebro - cerebellar dysfunction ; sensory ataxia ; and vestibular ataxia . examples of the diseases which are classifiable into spino - cerebellar ataxia or multiple system atrophy are hereditary olivo - ponto - cerebellar atrophy , hereditary cerebellar cortical atrophy , friedreich &# 39 ; s ataxia , machado - joseph diseases , ramsay hunt syndrome , hereditary dentatorubral - pallidoluysian atrophy , hereditary spastic paraplegia , shy - drager syndrome , cortical cerebellar atrophy , striato - nigral degeneration , marinesco - sjogren syndrome , alcoholic cortical cerebellar atrophy , paraneoplastic cerebellar atrophy associated with malignant tumor , toxic cerebellar atrophy caused by toxic substances , vitamin e deficiency due to mutation of a tocopherol transfer protein ( attp ) or lipid absorption disorder such as abetalipoproteinemia , cerebellar atrophy associated with endocrine disturbance and the like . examples of ataxia symptoms are motor ataxia , trunk ataxia , limb ataxia and the like , autonomic disturbance such as orthostatic hypotension , dysuria , hypohidrosis , sleep apnea , orthostatic syncope and the like , stiffness of lower extremity , ocular nystagmus , oculomotor nerve disorder , pyramidal tract dysfunction , extrapyramidal symptoms ( postural adjustment dysfunction , muscular rigidity , akinesia , tremors ), dysphagia , lingual atrophy , posterior funiculus symptom , muscle atrophy , muscle weakness , deep hyperreflexia , sensory disturbance , scoliosis , kyphoscoliosis , foot deformities , anarthria , dementia , manic state , decreased motivation for rehabilitation and the like . diseases amenable to treatment or suppression with compounds and methods of the invention a variety of disorders / diseases are believed to be caused or aggravated by oxidative stress affecting normal electron flow in the cells , such as mitochondrial disorders , impaired energy processing disorders , neurodegenerative diseases and diseases of aging , and can be treated or suppressed using the compounds and methods of the invention . non - limiting examples of oxidative stress disorders include , for example , mitochondrial disorders ( including inherited mitochondrial diseases ) such as alpers disease , barth syndrome , beta - oxidation defects , carnitine - acyl - carnitine deficiency , carnitine deficiency , creatine deficiency syndromes , co - enzyme q10 deficiency , complex i deficiency , complex ii deficiency , complex iii deficiency , complex iv deficiency , complex v deficiency , cox deficiency , chronic progressive external ophthalmoplegia ( cpeo ), cpt i deficiency , cpt ii deficiency , friedreich &# 39 ; s ataxia ( fa ), glutaric aciduria type ii , kearns - sayre syndrome ( kss ), lactic acidosis , long - chain acyl - coa dehydrongenase deficiency ( lcad ), lchad , leigh disease or syndrome , leigh - like syndrome , leber &# 39 ; s hereditary optic neuropathy ( lhon , also referred to as leber &# 39 ; s disease , leber &# 39 ; s optic atrophy ( loa ), or leber &# 39 ; s optic neuropathy ( lon )), lethal infantile cardiomyopathy ( lic ), luft disease , multiple acyl - coa dehydrogenase deficiency ( mad ), medium - chain acyl - coa dehydrongenase deficiency ( mcad ), mitochondrial myopathy , encephalopathy , lactacidosis , stroke ( melas ), myoclonic epilepsy with ragged red fibers ( merrf ), mitochondrial recessive ataxia syndrome ( miras ), mitochondrial cytopathy , mitochondrial dna depletion , mitochondrial encephalopathy , mitochondrial myopathy , myoneurogastointestinal disorder and encephalopathy ( mngie ), neuropathy , ataxia , and retinitis pigmentosa ( narp ), pearson syndrome , pyruvate carboxylase deficiency , pyruvate dehydrogenase deficiency , polg mutations , respiratory chain disorder , short - chain acyl - coa dehydrogenase deficiency ( scad ), schad , very long - chain acyl - coa dehydrongenase deficiency ( vlcad ); myopathies such as cardiomyopathy and encephalomyopathy ; neurodegenerative diseases such as parkinson &# 39 ; s disease , alzheimer &# 39 ; s disease , and amyotrophic lateral sclerosis ( als , also known as lou gehrig &# 39 ; s disease ); motor neuron diseases ; neurological diseases such as epilepsy ; age - associated diseases , particularly diseases for which coq10 has been proposed for treatment , such as macular degeneration , diabetes , metabolic syndrome , and cancer ( e . g . brain cancer ); genetic diseases such as huntington &# 39 ; s disease ( which is also a neurological disease ); mood disorders such as schizophrenia and bipolar disorder ; pervasive developmental disorders such as autistic disorder , asperger &# 39 ; s syndrome , childhood disintegrative disorder ( cdd ), rett &# 39 ; s disorder , and pdd - not otherwise specified ( pdd - nos ); cerebrovascular accidents such as stroke ; vision impairments such as those caused by neurodegenerative diseases of the eye such as optic neuropathy , leber &# 39 ; s hereditary optic neuropathy , dominant inherited juvenile optic atrophy , optic neuropathy caused by toxic agents , glaucoma , age - related macular degeneration ( both “ dry ” or non - exudative macular degeneration and “ wet ” or exudative macular degeneration ), stargardt &# 39 ; s macular dystrophy , diabetic retinopathy , diabetic maculopathy , retinopathy of prematurity , or ischemic reperfusion - related retinal injury ; disorders caused by energy impairment include diseases due to deprivation , poisoning or toxicity of oxygen , and qualitative or quantitative disruption in the transport of oxygen such as haemoglobionopathies , for example thalassemia or sickle cell anemia ; other diseases in which mitochondrial dysfunction is implicated such as excitoxic , neuronal injury , such as that associated with seizures , stroke and ischemia ; and other disorders including renal tubular acidosis ; attention deficit / hyperactivity disorder ( adhd ); neurodegenerative disorders resulting in hearing or balance impairment ; dominant optic atrophy ( doa ); maternally inherited diabetes and deafness ( midd ); chronic fatigue ; contrast - induced kidney damage ; contrast - induced retinopathy damage ; abetalipoproteinemia ; retinitis pigmentosum ; wolfram &# 39 ; s disease ; tourette syndrome ; cobalamin c defect ; methylmalonic aciduria ; glioblastoma ; down &# 39 ; s syndrome ; acute tubular necrosis ; muscular dystrophies ; leukodystrophies ; progressive supranuclear palsy ; spinal muscle atrophy ; hearing loss ( e . g . noise induced hearing loss ); and traumatic brain injury . for some disorders amenable to treatment with compounds and methods of the invention , the primary cause of the disorder is due to a defect in the respiratory chain or another defect preventing normal utilization of energy in mitochondria , cells , or tissue ( s ). non - limiting examples of disorders falling in this category include inherited mitochondrial diseases , such as myoclonic epilepsy with ragged red fibers ( merrf ), mitochondrial myopathy , encephalopathy , lactacidosis , and stroke ( melas ), leber &# 39 ; s hereditary optic neuropathy ( lhon , also referred to as leber &# 39 ; s disease , leber &# 39 ; s optic atrophy ( loa ), or leber &# 39 ; s optic neuropathy ( lon )), leigh disease or leigh syndrome , kearns - sayre syndrome ( kss ), and friedreich &# 39 ; s ataxia ( fa ). for some disorders amenable to treatment with compounds and methods of the invention , the primary cause of the disorder is not due to respiratory chain defects or other defects preventing normal utilization of energy in mitochondria , cells , or tissue ( s ); non - limiting examples of disorders falling in this category include stroke , cancer , and diabetes . however , these latter disorders are particularly aggravated by energy impairments , and are particularly amenable to treatment with compounds of the invention in order to ameliorate the condition . pertinent examples of such disorders include ischemic stroke and hemorrhagic stroke , where the primary cause of the disorder is due to impaired blood supply to the brain . while an ischemic episode caused by a thrombosis or embolism , or a hemorrhagic episode caused by a ruptured blood vessel , is not primarily caused by a defect in the respiratory chain or another metabolic defect preventing normal utilization of energy , oxidative stress plays a role in the ischemic cascade due to oxygen reperfusion injury following hypoxia ( this cascade occurs in heart attacks as well as in strokes ). accordingly , treatment with compounds and methods of the invention will mitigate the effects of the disease , disorder or condition . modulating one or more energy biomarkers , normalizing one or more energy biomarkers , or enhancing one or more energy biomarkers can also prove beneficial in such disorders both as a therapeutic measure and a prophylactic measure . for example , for a patient scheduled to undergo non - emergency repair of an aneurysm , enhancing energy biomarkers before and during the pre - operative can improve the patient &# 39 ; s prognosis should the aneurysm rupture before successful repair . the term “ oxidative stress disorder ” or “ oxidative stress disease ” encompass both diseases caused by oxidative stress and diseases aggravated by oxidative stress . the terms “ oxidative stress disorder ” or “ oxidative stress disease ” encompass both diseases and disorders where the primary cause of the disease is due to a defect in the respiratory chain or another defect preventing normal utilization of energy in mitochondria , cells , or tissue ( s ), and also diseases and disorders where the primary cause of the disease is not due to a defect in the respiratory chain or another defect preventing normal utilization of energy in mitochondria , cells , or tissue ( s ). the former set of diseases can be referred to as “ primary oxidative stress disorders ,” while the latter can be referred to as “ secondary oxidative stress disorders .” it should be noted that the distinction between “ diseases caused by oxidative stress ” and “ diseases aggravated by oxidative stress ” is not absolute ; a disease may be both a disease caused by oxidative stress and a disease aggravated by oxidative stress . the boundary between “ primary oxidative stress disorder ” and a “ secondary oxidative stress disorder ” is more distinct , provided that there is only one primary cause of a disease or disorder and that primary cause is known . bearing in mind the somewhat fluid boundary between diseases caused by oxidative stress and diseases aggravated by oxidative stress , mitochondrial diseases or disorders and impaired energy processing diseases and disorders tend to fall into the category of diseases caused by oxidative stress , while neurodegenerative disorders and diseases of aging tend to fall into the category of diseases aggravated by oxidative stress . mitochondrial diseases or disorders and impaired energy processing diseases and disorders are generally primary oxidative stress disorders , while neurodegenerative disorders and diseases of aging may be primary or secondary oxidative stress disorders . several readily measurable clinical markers are used to assess the metabolic state of patients with oxidative stress disorders . these markers can also be used as indicators of the efficacy of a given therapy , as the level of a marker is moved from the pathological value to the healthy value . these clinical markers include , but are not limited to , energy biomarkers such as lactic acid ( lactate ) levels , either in whole blood , plasma , cerebrospinal fluid , or cerebral ventricular fluid ; pyruvic acid ( pyruvate ) levels , either in whole blood , plasma , cerebrospinal fluid , or cerebral ventricular fluid ; lactate / pyruvate ratios , either in whole blood , plasma , cerebrospinal fluid , or cerebral ventricular fluid ; total , reduced or oxidized glutathione levels , or reduced / oxidized glutathione ratio either in whole blood , plasma , lymphocytes , cerebrospinal fluid , or cerebral ventricular fluid ; total , reduced or oxidized cysteine levels , or reduced / oxidized cysteine ratio either in whole blood , plasma , lymphocytes , cerebrospinal fluid , or cerebral ventricular fluid ; phosphocreatine levels , nadh ( nadh + h +) or nadph ( nadph + h +) levels ; nad or nadp levels ; atp levels ; anaerobic threshold ; reduced coenzyme q ( coqred ) levels ; oxidized coenzyme q ( coqox ) levels ; total coenzyme q ( coqtot ) levels ; oxidized cytochrome c levels ; reduced cytochrome c levels ; oxidized cytochrome c / reduced cytochrome c ratio ; acetoacetate levels , β - hydroxy butyrate levels , acetoacetate / β - hydroxy butyrate ratio , 8 - hydroxy - 2 ′- deoxyguanosine ( 8 - ohdg ) levels ; levels of reactive oxygen species ; and levels of oxygen consumption ( vo2 ), levels of carbon dioxide output ( vco2 ), and respiratory quotient ( vco2 / vo2 ). several of these clinical markers are measured routinely in exercise physiology laboratories , and provide convenient assessments of the metabolic state of a subject . in one embodiment of the invention , the level of one or more energy biomarkers in a patient suffering from an oxidative stress disorder , such as friedreich &# 39 ; s ataxia , leber &# 39 ; s hereditary optic neuropathy , melas , kss or coq10 deficiency , is improved to within two standard deviations of the average level in a healthy subject . in another embodiment of the invention , the level of one or more of these energy biomarkers in a patient suffering from an oxidative stress disorder , such as friedreich &# 39 ; s ataxia , leber &# 39 ; s hereditary optic neuropathy , melas , kss or coq10 deficiency is improved to within one standard deviation of the average level in a healthy subject . exercise intolerance can also be used as an indicator of the efficacy of a given therapy , where an improvement in exercise tolerance ( i . e ., a decrease in exercise intolerance ) indicates efficacy of a given therapy . several metabolic biomarkers have already been used to evaluate efficacy of coq10 , and these metabolic biomarkers can be monitored as energy biomarkers for use in the methods of the current invention . lactate , a product of the anaerobic metabolism of glucose , is removed by reduction to pyruvate in an aerobic setting or by oxidative metabolism , which is dependent on a functional mitochondrial respiratory chain . dysfunction of the respiratory chain may lead to inadequate removal of lactate and pyruvate from the circulation and elevated lactate / pyruvate ratios are observed in mitochondrial cytopathies ( see scriver c r , the metabolic and molecular bases of inherited disease , 7th ed ., new york : mcgraw - hill , health professions division , 1995 ; and munnich et al ., j . inherit . metab . dis . 15 ( 4 ): 448 - 55 ( 1992 )). blood lactate / pyruvate ratio ( chariot et al ., arch . pathol . lab . med . 118 ( 7 ): 695 - 7 ( 1994 )) is , therefore , widely used as a noninvasive test for detection of mitochondrial cytopathies ( see again scriver c r , the metabolic and molecular bases of inherited disease , 7th ed ., new york : mcgraw - hill , health professions division , 1995 ; and munnich et al ., j . inherit . metab . dis . 15 ( 4 ): 448 - 55 ( 1992 )) and toxic mitochondrial myopathies ( chariot et al ., arthritis rheum . 37 ( 4 ): 583 - 6 ( 1994 )). changes in the redox state of liver mitochondria can be investigated by measuring the arterial ketone body ratio ( acetoacetate / 3 - hydroxybutyrate : akbr ) ( ueda et al ., j . cardiol . 29 ( 2 ): 95 - 102 ( 1997 )). urinary excretion of 8 - hydroxy - 2 ′- deoxyguanosine ( 8 - ohdg ) often has been used as a biomarker to assess the extent of repair of ros - induced dna damage in both clinical and occupational settings ( erhola et al ., febs lett . 409 ( 2 ): 287 - 91 ( 1997 ); honda et al ., leuk . res . 24 ( 6 ): 461 - 8 ( 2000 ); pilger et al ., free radic . res . 35 ( 3 ): 273 - 80 ( 2001 ); kim et al . environ health perspect 112 ( 6 ): 666 - 71 ( 2004 )). magnetic resonance spectroscopy ( mrs ) has been useful in the diagnoses of mitochondrial cytopathy by demonstrating elevations in cerebrospinal fluid ( csf ) and cortical white matter lactate using proton mrs ( 1h - mrs ) ( kaufmann et al ., neurology 62 ( 8 ): 1297 - 302 ( 2004 )). phosphorous mrs ( 31p - mrs ) has been used to demonstrate low levels of cortical phosphocreatine ( pcr ) ( matthews et al ., ann . neurol . 29 ( 4 ): 435 - 8 ( 1991 )), and a delay in pcr recovery kinetics following exercise in skeletal muscle ( matthews et al ., ann . neurol . 29 ( 4 ): 435 - 8 ( 1991 ); barbiroli et al ., j . neurol . 242 ( 7 ): 472 - 7 ( 1995 ); fabrizi et al ., j . neurol . sci . 137 ( 1 ): 20 - 7 ( 1996 )). a low skeletal muscle pcr has also been confirmed in patients with mitochondrial cytopathy by direct biochemical measurements . exercise testing is particularly helpful as an evaluation and screening tool in mitochondrial myopathies . one of the hallmark characteristics of mitochondrial myopathies is a reduction in maximal whole body oxygen consumption ( vo2max ) ( taivassalo et al ., brain 126 ( pt 2 ): 413 - 23 ( 2003 )). given that vo2max is determined by cardiac output ( qc ) and peripheral oxygen extraction ( arterial - venous total oxygen content ) difference , some mitochondrial cytopathies affect cardiac function where delivery can be altered ; however , most mitochondrial myopathies show a characteristic deficit in peripheral oxygen extraction ( a - v o2 difference ) and an enhanced oxygen delivery ( hyperkinetic circulation ) ( taivassalo et al ., brain 126 ( pt 2 ): 413 - 23 ( 2003 )). this can be demonstrated by a lack of exercise induced deoxygenation of venous blood with direct av balance measurements ( taivassalo et al ., ann . neurol . 51 ( 1 ): 38 - 44 ( 2002 )) and non - invasively by near infrared spectroscopy ( lynch et al ., muscle nerve 25 ( 5 ): 664 - 73 ( 2002 ); van beekvelt et al ., ann . neurol . 46 ( 4 ): 667 - 70 ( 1999 )). several of these energy biomarkers are discussed in more detail as follows . it should be emphasized that , while certain energy biomarkers are discussed and enumerated herein , the invention is not limited to modulation , normalization or enhancement of only these enumerated energy biomarkers . lactic acid ( lactate ) levels : mitochondrial dysfunction typically results in abnormal levels of lactic acid , as pyruvate levels increase and pyruvate is converted to lactate to maintain capacity for glycolysis . mitochondrial dysfunction can also result in abnormal levels of nadh + h +, nadph + h +, nad , or nadp , as the reduced nicotinamide adenine dinucleotides are not efficiently processed by the respiratory chain . lactate levels can be measured by taking samples of appropriate bodily fluids such as whole blood , plasma , or cerebrospinal fluid . using magnetic resonance , lactate levels can be measured in virtually any volume of the body desired , such as the brain . measurement of cerebral lactic acidosis using magnetic resonance in melas patients is described in kaufmann et al ., neurology 62 ( 8 ): 1297 ( 2004 ). values of the levels of lactic acid in the lateral ventricles of the brain are presented for two mutations resulting in melas , a3243g and a8344g . whole blood , plasma , and cerebrospinal fluid lactate levels can be measured by commercially available equipment such as the ysi 2300 stat plus glucose & amp ; lactate analyzer ( ysi life sciences , ohio ). nad , nadp , nadh and nadph levels : measurement of nad , nadp , nadh ( nadh + h +) or nadph ( nadph + h +) can be measured by a variety of fluorescent , enzymatic , or electrochemical techniques , e . g ., the electrochemical assay described in us 2005 / 0067303 . gsh , gssg , cys , and cyss levels : briefly , plasma levels of gsh , gssg , cys , and cyss are used to calculate the in vivo e h values . samples are collected using the procedure of jones et al ( 2009 free radical biology & amp ; medicine 47 ( 10 ) pp . 1329 - 1338 ), and bromobimane is used to alkylate free thiols and hplc and either electrochemical or msms to separate , detect , and quantify the molecules . as described in more detail in u . s . provisional patent application no . 61 / 698 , 431 filed sep . 7 , 2012 , and u . s . provisional patent application under ser . no . 61 / 792 , 797 filed mar . 15 , 2013 , we have developed a method for different experimental parameters to analyze the most common monothiols and disulfide ( cystine , cysteine , reduced ( gsh ) and oxidized glutathione ( gssg )) present in human plasma , and using bathophenanthroline disulfonic acid as the internal standard ( is ). complete separation of all the targets analytes and is at 35 . 0 on a c18 rp column ( 250 mm × 4 . 6 mm , 3 micron ) was achieved using 0 . 2 % tfa : acetonitrile as a mobile phase pumped at the rate of 0 . 6 ml min − 1 using electrochemical detector in dc mode at the detector potential of 1475 mv . oxygen consumption ( vo2 or vo2 ), carbon dioxide output ( vco2 or vco2 ), and respiratory quotient ( vco2 / vo2 ): vo2 is usually measured either while resting ( resting vo2 ) or at maximal exercise intensity ( vo2 max ). optimally , both values will be measured . however , for severely disabled patients , measurement of vo2 max may be impractical . measurement of both forms of vo2 is readily accomplished using standard equipment from a variety of vendors , e . g . korr medical technologies , inc . ( salt lake city , utah ). vco2 can also be readily measured , and the ratio of vco2 to vo2 under the same conditions ( vco2 / vo2 , either resting or at maximal exercise intensity ) provides the respiratory quotient ( rq ). oxidized cytochrome c , reduced cytochrome c , and ratio of oxidized cytochrome c to reduced cytochrome c : cytochrome c parameters , such as oxidized cytochrome c levels ( cyt cox ), reduced cytochrome c levels ( cyt cred ), and the ratio of oxidized cytochrome c / reduced cytochrome c ratio ( cyt cox )/( cyt cred ), can be measured by in vivo near infrared spectroscopy . see , e . g ., rolfe , p ., “ in vivo near - infrared spectroscopy ,” annu . rev . biomed . eng . 2 : 715 - 54 ( 2000 ) and strangman et al ., “ non - invasive neuroimaging using near - infrared light ” biol . psychiatry 52 : 679 - 93 ( 2002 ). exercise tolerance / exercise intolerance : exercise intolerance is defined as “ the reduced ability to perform activities that involve dynamic movement of large skeletal muscles because of symptoms of dyspnea or fatigue ” ( piña et al ., circulation 107 : 1210 ( 2003 )). exercise intolerance is often accompanied by myoglobinuria , due to breakdown of muscle tissue and subsequent excretion of muscle myoglobin in the urine . various measures of exercise intolerance can be used , such as time spent walking or running on a treadmill before exhaustion , time spent on an exercise bicycle ( stationary bicycle ) before exhaustion , and the like . treatment with the compounds or methods of the invention can result in about a 10 % or greater improvement in exercise tolerance ( for example , about a 10 % or greater increase in time to exhaustion , e . g . from 10 minutes to 11 minutes ), about a 20 % or greater improvement in exercise tolerance , about a 30 % or greater improvement in exercise tolerance , about a 40 % or greater improvement in exercise tolerance , about a 50 % or greater improvement in exercise tolerance , about a 75 % or greater improvement in exercise tolerance , or about a 100 % or greater improvement in exercise tolerance . while exercise tolerance is not , strictly speaking , an energy biomarker , for the purposes of the invention , modulation , normalization , or enhancement of energy biomarkers includes modulation , normalization , or enhancement of exercise tolerance . similarly , tests for normal and abnormal values of pyruvic acid ( pyruvate ) levels , lactate / pyruvate ratio , atp levels , anaerobic threshold , reduced coenzyme q ( coqred ) levels , oxidized coenzyme q ( coqox ) levels , total coenzyme q ( coqtot ) levels , oxidized cytochrome c levels , reduced cytochrome c levels , oxidized cytochrome c / reduced cytochrome c ratio , gsh and cysteine reduced , oxidized , total levels and ratio , acetoacetate levels , β - hydroxy butyrate levels , acetoacetate / β - hydroxy butyrate ratio , 8 - hydroxy - 2 ′- deoxyguanosine ( 8 - ohdg ) levels , and levels of reactive oxygen species are known in the art and can be used to evaluate efficacy of the compounds and methods of the invention . ( for the purposes of the invention , modulation , normalization , or enhancement of energy biomarkers includes modulation , normalization , or enhancement of anaerobic threshold .) table 1 , following , illustrates the effect that various dysfunctions can have on biochemistry and energy biomarkers . it also indicates the physical effect ( such as a disease symptom or other effect of the dysfunction ) typically associated with a given dysfunction . it should be noted that any of the energy biomarkers listed in the table , in addition to energy biomarkers enumerated elsewhere , can also be modulated , enhanced , or normalized by the compounds and methods of the invention . rq = respiratory quotient ; bmr = basal metabolic rate ; hr ( co )= heart rate ( cardiac output ); t = body temperature ( preferably measured as core temperature ); at = anaerobic threshold ; ph = blood ph ( venous and / or arterial ). treatment of a subject afflicted by an oxidative stress disorder in accordance with the methods of the invention may result in the inducement of a reduction or alleviation of symptoms in the subject , e . g ., to halt the further progression of the disorder . partial or complete suppression of the oxidative stress disorder can result in a lessening of the severity of one or more of the symptoms that the subject would otherwise experience . for example , partial suppression of melas could result in reduction in the number of stroke - like or seizure episodes suffered . any one or any combination of the energy biomarkers described herein provide conveniently measurable benchmarks by which to gauge the effectiveness of treatment or suppressive therapy . additionally , other energy biomarkers are known to those skilled in the art and can be monitored to evaluate the efficacy of treatment or suppressive therapy . in addition to monitoring energy biomarkers to assess the status of treatment or suppression of oxidative stress disorders , the compounds of the invention can be used in subjects or patients to modulate one or more energy biomarkers . modulation of energy biomarkers can be done to normalize energy biomarkers in a subject , or to enhance energy biomarkers in a subject . normalization of one or more energy biomarkers is defined as either restoring the level of one or more such energy biomarkers to normal or near - normal levels in a subject whose levels of one or more energy biomarkers show pathological differences from normal levels ( i . e ., levels in a healthy subject ), or to change the levels of one or more energy biomarkers to alleviate pathological symptoms in a subject . depending on the nature of the energy biomarker , such levels may show measured values either above or below a normal value . for example , a pathological lactate level is typically higher than the lactate level in a normal ( i . e ., healthy ) person , and a decrease in the level may be desirable . a pathological atp level is typically lower than the atp level in a normal ( i . e ., healthy ) person , and an increase in the level of atp may be desirable . accordingly , normalization of energy biomarkers can involve restoring the level of energy biomarkers to within about at least two standard deviations of normal in a subject , more preferably to within about at least one standard deviation of normal in a subject , to within about at least one - half standard deviation of normal , or to within about at least one - quarter standard deviation of normal . enhancement of the level of one or more energy biomarkers is defined as changing the extant levels of one or more energy biomarkers in a subject to a level which provides beneficial or desired effects for the subject . for example , a person undergoing strenuous effort or prolonged vigorous physical activity , such as mountain climbing , could benefit from increased atp levels or decreased lactate levels . as described above , normalization of energy biomarkers may not achieve the optimum state for a subject with an oxidative stress disease , and such subjects can also benefit from enhancement of energy biomarkers . examples of subjects who could benefit from enhanced levels of one or more energy biomarkers include , but are not limited to , subjects undergoing strenuous or prolonged physical activity , subjects with chronic energy problems , or subjects with chronic respiratory problems . such subjects include , but are not limited to , pregnant females , particularly pregnant females in labor ; neonates , particularly premature neonates ; subjects exposed to extreme environments , such as hot environments ( temperatures routinely exceeding about 85 - 86 degrees fahrenheit or about 30 degrees celsius for about 4 hours daily or more ), cold environments ( temperatures routinely below about 32 degrees fahrenheit or about 0 degrees celsius for about 4 hours daily or more ), or environments with lower - than - average oxygen content , higher - than - average carbon dioxide content , or higher - than - average levels of air pollution ( airline travelers , flight attendants , subjects at elevated altitudes , subjects living in cities with lower - than - average air quality , subjects working in enclosed environments where air quality is degraded ); subjects with lung diseases or lower - than - average lung capacity , such as tubercular patients , lung cancer patients , emphysema patients , and cystic fibrosis patients ; subjects recovering from surgery or illness ; elderly subjects , including elderly subjects experiencing decreased energy ; subjects suffering from chronic fatigue , including chronic fatigue syndrome ; subjects undergoing acute trauma ; subjects in shock ; subjects requiring acute oxygen administration ; subjects requiring chronic oxygen administration ; or other subjects with acute , chronic , or ongoing energy demands who can benefit from enhancement of energy biomarkers . accordingly , when an increase in a level of one or more energy biomarkers is beneficial to a subject , enhancement of the one or more energy biomarkers can involve increasing the level of the respective energy biomarker or energy biomarkers to about at least one - quarter standard deviation above normal , about at least one - half standard deviation above normal , about at least one standard deviation above normal , or about at least two standard deviations above normal . alternatively , the level of the one or more energy biomarkers can be increased by about at least 10 % above the subject &# 39 ; s level of the respective one or more energy biomarkers before enhancement , by about at least 20 % above the subject &# 39 ; s level of the respective one or more energy biomarkers before enhancement , by about at least 30 % above the subject &# 39 ; s level of the respective one or more energy biomarkers before enhancement , by about at least 40 % above the subject &# 39 ; s level of the respective one or more energy biomarkers before enhancement , by about at least 50 % above the subject &# 39 ; s level of the respective one or more energy biomarkers before enhancement , by about at least 75 % above the subject &# 39 ; s level of the respective one or more energy biomarkers before enhancement , or by about at least 100 % above the subject &# 39 ; s level of the respective one or more energy biomarkers before enhancement . when a decrease in a level of one or more energy biomarkers is desired to enhance one or more energy biomarkers , the level of the one or more energy biomarkers can be decreased by an amount of about at least one - quarter standard deviation of normal in a subject , decreased by about at least one - half standard deviation of normal in a subject , decreased by about at least one standard deviation of normal in a subject , or decreased by about at least two standard deviations of normal in a subject . alternatively , the level of the one or more energy biomarkers can be decreased by about at least 10 % below the subject &# 39 ; s level of the respective one or more energy biomarkers before enhancement , by about at least 20 % below the subject &# 39 ; s level of the respective one or more energy biomarkers before enhancement , by about at least 30 % below the subject &# 39 ; s level of the respective one or more energy biomarkers before enhancement , by about at least 40 % below the subject &# 39 ; s level of the respective one or more energy biomarkers before enhancement , by about at least 50 % below the subject &# 39 ; s level of the respective one or more energy biomarkers before enhancement , by about at least 75 % below the subject &# 39 ; s level of the respective one or more energy biomarkers before enhancement , or by about at least 90 % below the subject &# 39 ; s level of the respective one or more energy biomarkers before enhancement . the compounds of the invention can also be used in research applications . they can be used in in vitro , in vivo , or ex vivo experiments to modulate one or more energy biomarkers in an experimental system . such experimental systems can be cell samples , tissue samples , cell components or mixtures of cell components , partial organs , whole organs , or organisms . any one or more of the compounds of formula i or ii can be used in experimental systems or research applications . such research applications can include , but are not limited to , use as assay reagents , elucidation of biochemical pathways , or evaluation of the effects of other agents on the metabolic state of the experimental system in the presence / absence of one or more compounds of the invention . additionally , the compounds of the invention can be used in biochemical tests or assays . such tests can include incubation of one or more compounds of the invention with a tissue or cell sample from a subject to evaluate a subject &# 39 ; s potential response ( or the response of a specific subset of subjects ) to administration of said one or more compounds , or to determine which compound of the invention produces the optimum effect in a specific subject or subset of subjects . one such test or assay would involve 1 ) obtaining a cell sample or tissue sample from a subject in which modulation of one or more energy biomarkers can be assayed ; 2 ) administering one or more compounds of the invention to the cell sample or tissue sample ; and 3 ) determining the amount of modulation of the one or more energy biomarkers after administration of the one or more compounds , compared to the status of the energy biomarker prior to administration of the one or more compounds . another such test or assay would involve 1 ) obtaining a cell sample or tissue sample from a subject in which modulation of one or more energy biomarkers can be assayed ; 2 ) administering at least two compounds of the invention to the cell sample or tissue sample ; 3 ) determining the amount of modulation of the one or more energy biomarkers after administration of the at least two compounds , compared to the status of the energy biomarker prior to administration of the at least two compounds , and 4 ) selecting a compound or compounds for use in treatment , suppression , or modulation based on the amount of modulation determined in step 3 . the compounds described herein can be formulated as pharmaceutical compositions by formulation with additives such as pharmaceutically acceptable excipients , pharmaceutically acceptable carriers , and pharmaceutically acceptable vehicles . suitable pharmaceutically acceptable excipients , carriers and vehicles include processing agents and drug delivery modifiers and enhancers , such as , for example , calcium phosphate , magnesium stearate , talc , monosaccharides , disaccharides , starch , gelatin , cellulose , methyl cellulose , sodium carboxymethyl cellulose , dextrose , hydroxypropyl - β - cyclodextrin , polyvinylpyrrolidinone , low melting waxes , ion exchange resins , and the like , as well as combinations of any two or more thereof . other suitable pharmaceutically acceptable excipients are described in “ remington &# 39 ; s pharmaceutical sciences ,” mack pub . co ., new jersey ( 1991 ), and “ remington : the science and practice of pharmacy ,” lippincott williams & amp ; wilkins , philadelphia , 20th edition ( 2003 ) and 21st edition ( 2005 ), incorporated herein by reference . a pharmaceutical composition can comprise a unit dose formulation , where the unit dose is a dose sufficient to have a therapeutic or suppressive effect or an amount effective to modulate , normalize , or enhance an energy biomarker . the unit dose may be sufficient as a single dose to have a therapeutic or suppressive effect or an amount effective to modulate , normalize , or enhance an energy biomarker . alternatively , the unit dose may be a dose administered periodically in a course of treatment or suppression of a disorder , or to modulate , normalize , or enhance an energy biomarker . pharmaceutical compositions containing the compounds of the invention may be in any form suitable for the intended method of administration , including , for example , a solution , a suspension , or an emulsion . liquid carriers are typically used in preparing solutions , suspensions , and emulsions . liquid carriers contemplated for use in the practice of the present invention include , for example , water , saline , pharmaceutically acceptable organic solvent ( s ), pharmaceutically acceptable oils or fats , and the like , as well as mixtures of two or more thereof . the liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers , emulsifiers , nutrients , buffers , preservatives , suspending agents , thickening agents , viscosity regulators , stabilizers , and the like . suitable organic solvents include , for example , monohydric alcohols , such as ethanol , and polyhydric alcohols , such as glycols . suitable oils include , for example , soybean oil , coconut oil , olive oil , safflower oil , cottonseed oil , and the like . for parenteral administration , the carrier can also be an oily ester such as ethyl oleate , isopropyl myristate , and the like . compositions of the present invention may also be in the form of microparticles , microcapsules , liposomal encapsulates , and the like , as well as combinations of any two or more thereof . time - release or controlled release delivery systems may be used , such as a diffusion controlled matrix system or an erodible system , as described for example in : lee , “ diffusion - controlled matrix systems ”, pp . 155 - 198 and ron and langer , “ erodible systems ”, pp . 199 - 224 , in “ treatise on controlled drug delivery ”, a . kydonieus ed ., marcel dekker , inc ., new york 1992 . the matrix may be , for example , a biodegradable material that can degrade spontaneously in situ and in vivo for , example , by hydrolysis or enzymatic cleavage , e . g ., by proteases . the delivery system may be , for example , a naturally occurring or synthetic polymer or copolymer , for example in the form of a hydrogel . exemplary polymers with cleavable linkages include polyesters , polyorthoesters , polyanhydrides , polysaccharides , poly ( phosphoesters ), polyamides , polyurethanes , poly ( imidocarbonates ) and poly ( phosphazenes ). the compounds of the invention may be administered enterally , orally , parenterally , sublingually , by inhalation ( e . g . as mists or sprays ), rectally , or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers , adjuvants , and vehicles as desired . for example , suitable modes of administration include oral , subcutaneous , transdermal , transmucosal , iontophoretic , intravenous , intraarterial , intramuscular , intraperitoneal , intranasal ( e . g . via nasal mucosa ), subdural , rectal , gastrointestinal , and the like , and directly to a specific or affected organ or tissue . for delivery to the central nervous system , spinal and epidural administration , or administration to cerebral ventricles , can be used . topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices . the term parenteral as used herein includes subcutaneous injections , intravenous , intramuscular , intrasternal injection , or infusion techniques . the compounds are mixed with pharmaceutically acceptable carriers , adjuvants , and vehicles appropriate for the desired route of administration . oral administration is a preferred route of administration , and formulations suitable for oral administration are preferred formulations . the compounds described for use herein can be administered in solid form , in liquid form , in aerosol form , or in the form of tablets , pills , powder mixtures , capsules , granules , injectables , creams , solutions , suppositories , enemas , colonic irrigations , emulsions , dispersions , food premixes , and in other suitable forms . the compounds can also be administered in liposome formulations . the compounds can also be administered as prodrugs , where the prodrug undergoes transformation in the treated subject to a form which is therapeutically effective . additional methods of administration are known in the art . in some embodiments of the invention , especially those embodiments where a formulation is used for injection or other parenteral administration including the routes listed herein , but also including embodiments used for oral , gastric , gastrointestinal , or enteric administration , the formulations and preparations used in the methods of the invention are sterile . sterile pharmaceutical formulations are compounded or manufactured according to pharmaceutical - grade sterilization standards ( united states pharmacopeia chapters 797 , 1072 , and 1211 ; california business & amp ; professions code 4127 . 7 ; 16 california code of regulations 1751 , 21 code of federal regulations 211 ) known to those of skill in the art . injectable preparations , for example , sterile injectable aqueous or oleaginous suspensions , may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents . the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent , for example , as a solution in propylene glycol . among the acceptable vehicles and solvents that may be employed are water , ringer &# 39 ; s solution , and isotonic sodium chloride solution . in addition , sterile , fixed oils are conventionally employed as a solvent or suspending medium . for this purpose any bland fixed oil may be employed including synthetic mono - or diglycerides . in addition , fatty acids such as oleic acid find use in the preparation of injectables . solid dosage forms for oral administration may include capsules , tablets , pills , powders , and granules . in such solid dosage forms , the active compound may be admixed with at least one inert diluent such as sucrose , lactose , or starch . such dosage forms may also comprise additional substances other than inert diluents , e . g ., lubricating agents such as magnesium stearate . in the case of capsules , tablets , and pills , the dosage forms may also comprise buffering agents . tablets and pills can additionally be prepared with enteric coatings . liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions , solutions , suspensions , syrups , and elixirs containing inert diluents commonly used in the art , such as water . such compositions may also comprise adjuvants , such as wetting agents , emulsifying and suspending agents , cyclodextrins , and sweetening , flavoring , and perfuming agents . the compounds of the present invention can also be administered in the form of liposomes . as is known in the art , liposomes are generally derived from phospholipids or other lipid substances . liposomes are formed by mono - or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium . any non - toxic , physiologically acceptable and metabolizable lipid capable of forming liposomes can be used . the present compositions in liposome form can contain , in addition to a compound of the present invention , stabilizers , preservatives , excipients , and the like . the preferred lipids are the phospholipids and phosphatidyl cholines ( lecithins ), both natural and synthetic . methods to form liposomes are known in the art . see , for example , prescott , ed ., methods in cell biology , volume xiv , academic press , new york , n . w ., p . 33 et seq ( 1976 ). the invention also provides articles of manufacture and kits containing materials useful for treating or suppressing oxidative stress disorders . the invention also provides kits comprising any one or more of the compounds of formula i or ii . in some embodiments , the kit of the invention comprises the container described above . in other aspects , the kits may be used for any of the methods described herein , including , for example , to treat an individual with a mitochondrial disorder , or to suppress a mitochondrial disorder in an individual . the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host to which the active ingredient is administered and the particular mode of administration . it will be understood , however , that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed , the age , body weight , body area , body mass index ( bmi ), general health , sex , diet , time of administration , route of administration , rate of excretion , drug combination , and the type , progression , and severity of the particular disease undergoing therapy . the pharmaceutical unit dosage chosen is usually fabricated and administered to provide a defined final concentration of drug in the blood , tissues , organs , or other targeted region of the body . the therapeutically effective amount or effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician . examples of dosages which can be used are a therapeutically effective amount or effective amount within the dosage range of about 0 . 1 mg / kg to about 300 mg / kg body weight , or within about 1 . 0 mg / kg to about 100 mg / kg body weight , or within about 1 . 0 mg / kg to about 50 mg / kg body weight , or within about 1 . 0 mg / kg to about 30 mg / kg body weight , or within about 1 . 0 mg / kg to about 10 mg / kg body weight , or within about 10 mg / kg to about 100 mg / kg body weight , or within about 50 mg / kg to about 150 mg / kg body weight , or within about 100 mg / kg to about 200 mg / kg body weight , or within about 150 mg / kg to about 250 mg / kg body weight , or within about 200 mg / kg to about 300 mg / kg body weight , or within about 250 mg / kg to about 300 mg / kg body weight . compounds of the present invention may be administered in a single daily dose , or the total daily dosage may be administered in divided dosage of two , three or four times daily . while the compounds of the invention can be administered as the sole active pharmaceutical agent , they can also be used in combination with one or more other agents used in the treatment or suppression of disorders . representative agents useful in combination with the compounds of the invention for the treatment or suppression of mitochondrial diseases include , but are not limited to , coenzyme q , vitamin e , idebenone , mitoq , vitamins , nac , and antioxidant compounds . when additional active agents are used in combination with the compounds of the present invention , the additional active agents may generally be employed in therapeutic amounts as indicated in the physicians &# 39 ; desk reference ( pdr ) 53rd edition ( 1999 ), or such therapeutically useful amounts as would be known to one of ordinary skill in the art . the compounds of the invention and the other therapeutically active agents can be administered at the recommended maximum clinical dosage or at lower doses . dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration , severity of the disease and the response of the patient . when administered in combination with other therapeutic agents , the therapeutic agents can be formulated as separate compositions that are given at the same time or different times , or the therapeutic agents can be given as a single composition . the invention will be further understood by the following nonlimiting examples . the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures . it will be appreciated that where typical or preferred process conditions ( i . e ., reaction temperatures , times , mole ratios of reactants , solvents , pressures , etc .) are given , other process conditions can also be used unless otherwise stated . optimum reaction conditions may vary with the particular reactants or solvent used , but such conditions can be determined by one skilled in the art by routine optimization procedures . the terms “ solvent ”, “ inert organic solvent ” or “ inert solvent ” mean a solvent inert under the conditions of the reaction being described in conjunction therewith . solvents employed in synthesis of the compounds of the invention include , for example , methanol (“ meoh ”), acetone , water , acetonitrile , 1 , 4 - dioxane , dimethylformamide (“ dmf ”), benzene , toluene , xylene , tetrahydrofuran (“ thf ”), chloroform , methylene chloride ( or dichloromethane , (“ dcm ”)), diethyl ether , pyridine and the like , as well as mixtures thereof . unless specified to the contrary , the solvents used in the reactions of the present invention are inert organic solvents . the term “ q . s .” means adding a quantity sufficient to achieve a stated function , e . g ., to bring a solution to the desired volume ( i . e ., 100 %). the compounds herein are synthesized by an appropriate combination of generally well - known synthetic methods . techniques useful in synthesizing the compounds herein are both readily apparent and accessible to those of skill in the relevant art in light of the teachings described herein . the discussion below is offered to illustrate certain of the diverse methods available for use in assembling the compounds herein . however , the discussion is not intended to define the scope of reactions or reaction sequences that are useful in preparing the compounds herein . a non - limiting , illustrative example of a synthesis of 2 , 3 , 5 - trimethyl - 6 -( 12 - hydroxy - 5 , 10 - dodecadiynyl )- 1 , 4 - benzoquinone is shown in “ quinone compounds , and their use ” by terao , shinji and maki , yoshitaka , eur . pat . appl ., 103361 , 21 mar . 1984 , which is herein incorporated by reference in its entirety . other compounds of the invention may be synthesized using analogous methods . u . s . pat . no . 4 , 393 , 075 , which is herein incorporated by reference in its entirety , provides further examples of synthetic methods useful in the synthesis of compounds of the invention . the reduced ( hydroxy ) form may readily be converted to the oxidized ( quinone ) form using methods known in the art . see e . g . air , silica miller et al pct intl appl 2006130775 7 dec . 2006 . the oxidized ( quinone ) form may readily be converted to the reduced hydroxy form using methods known in the art . see , e . g . zn , acoh fuchs et al ejoc 6 ( 2009 ) 833 - 40 . synthetic methods for other compounds of the invention will be apparent to one skilled in the art in view of the illustrative examples above . screening compounds of the invention in human dermal fibroblasts from friedreich &# 39 ; s ataxia patients test samples and solvent controls were tested for their ability to rescue frda fibroblasts stressed by addition of l - buthionine -( s , r )- sulfoximine ( bso ), as described in jauslin et al ., hum . mol . genet . 11 ( 24 ): 3055 ( 2002 ), jauslin et al ., faseb j . 17 : 1972 - 4 ( 2003 ), and international patent application wo 2004 / 003565 . human dermal fibroblasts from friedreich &# 39 ; s ataxia patients have been shown to be hypersensitive to inhibition of the de novo synthesis of glutathione ( gsh ) with l - buthionine -( s , r )- sulfoximine ( bso ), a specific inhibitor of gsh synthetase ( jauslin et al ., hum . mol . genet . 11 ( 24 ): 3055 ( 2002 )). this specific bso - mediated cell death can be prevented by administration of antioxidants or molecules involved in the antioxidant pathway , such as alpha - tocopherol , selenium , or small molecule glutathione peroxidase mimetics . however , antioxidants differ in their potency , i . e . the concentration at which they are able to rescue bso - stressed frda fibroblasts . mem ( a medium enriched in amino acids and vitamins , catalog no . 1 - 31f24 - i ) and medium 199 ( m199 , catalog no . 1 - 21f22 - i ) with earle &# 39 ; s balanced salts , without phenol red , were purchased from bioconcept . fetal calf serum was obtained from paa laboratories . basic fibroblast growth factor and epidermal growth factor were purchased from peprotech . 2 , 3 , 5 - trimethyl - 6 -( 12 - hydroxy - 5 , 10 - dodecadiynyl )- 1 , 4 - benzoquinone , penicillin - streptomycin - glutamine mix , l - buthionine ( s , r )- sulfoximine , and insulin from bovine pancreas were purchased from sigma . calcein am was purchased from molecular probes . cell culture medium was made by combining 125 ml m199 ebs , 50 ml fetal calf serum , 100 u / ml penicillin , 100 microgram / ml streptomycin , 2 mm glutamine , 10 microgram / ml insulin , 10 ng / ml egf , and 10 ng / ml bfgf ; mem ebs was added to make the volume up to 500 ml . a 10 mm bso solution was prepared by dissolving 444 mg bso in 200 ml of medium ( invitrogen , carlsbad , ca .) with subsequent filter - sterilization . during the course of the experiments , this solution was stored at + 4 ° c . the cells were obtained from the coriell cell repositories ( camden , n . j . ; repository number gm04078 ) and grown in 10 cm tissue culture plates . every third day , they were split at a 1 : 3 ratio . the test samples were supplied in 1 . 5 ml glass vials . the compounds were diluted with dmso , ethanol or pbs to result in a 5 mm stock solution . once dissolved , they were stored at − 20 ° c . a culture with frda fibroblasts was started from a 1 ml vial with approximately 500 , 000 cells stored in liquid nitrogen . cells were propagated in 10 cm cell culture dishes by splitting every third day in a ratio of 1 : 3 until nine plates were available . once confluent , fibroblasts were harvested . for 54 micro titer plates ( 96 well - mtp ) a total of 14 . 3 million cells ( passage eight ) were re - suspended in 480 ml medium , corresponding to 100 microliters medium with 3 , 000 cells / well . the remaining cells were distributed in 10 cm cell culture plates ( 500 , 000 cells / plate ) for propagation . the plates were incubated overnight at 37 ° c . in an atmosphere with 95 % humidity and 5 % co2 to allow attachment of the cells to the culture plate . mtp medium ( 243 microliters ) was added to a well of the microtiter plate . the test compounds were unfrozen , and 7 . 5 microliters of a 5 mm stock solution was dissolved in the well containing 243 microliters medium , resulting in a 150 micromolar master solution . serial dilutions from the master solution were made . the period between the single dilution steps was kept as short as possible ( generally less than 30 seconds ). plates were kept overnight in the cell culture incubator . the next day , 10 microliters of a 10 mm bso solution were added to the wells , resulting in a 1 mm final bso concentration . forty - eight hours later , three plates were examined under a phase - contrast microscope to verify that the cells in the 0 % control ( wells e1 - h1 ) were clearly dead . the medium from all plates was discarded , and the remaining liquid was removed by gently tapping the plate inversed onto a paper towel . 100 microliters of pbs containing 1 . 2 microm calcein am were then added to each well . the plates were incubated for 50 - 70 minutes at room temperature . after that time the pbs was discarded , the plate tapped gently on a paper towel and fluorescence ( excitation / emission wavelengths of 485 nm and 525 nm , respectively ) was read on a gemini fluorescence reader . data was imported into microsoft excel ( excel is a registered trademark of microsoft corporation for a spreadsheet program ) and excelfit was used to calculate the ec50 concentration for each compound . the compounds were tested three times , i . e ., the experiment was performed three times , the passage number of the cells increasing by one with every repetition . the solvents ( dmso , ethanol , pbs ) neither had a detrimental effect on the viability of non - bso treated cells nor did they have a beneficial influence on bso - treated fibroblasts even at the highest concentration tested ( 1 %). none of the compounds showed auto - fluorescence . the viability of non - bso treated fibroblasts was set as 100 %, and the viability of the bso - and compound - treated cells was calculated as relative to this value . 2 , 3 , 5 - trimethyl - 6 -( 12 - hydroxy - 5 , 10 - dodecadiynyl )- 1 , 4 - benzoquinone exhibited protection against frda with an ec50 of less than about 100 nm . 2 , 3 , 5 - trimethyl - 6 -( 12 - hydroxy - 5 , 10 - dodecadiynyl )- 1 , 4 - benzoquinone was tested using a screen similar to the one described in example 1 , but substituting frda cells with huntington &# 39 ; s cells obtained from the coriell cell repositories ( camden , n . j . ; repository number gm 04281 ). the compound was tested for its ability to rescue human dermal fibroblasts from huntington &# 39 ; s patients from oxidative stress . 2 , 3 , 5 - trimethyl - 6 -( 12 - hydroxy - 5 , 10 - dodecadiynyl )- 1 , 4 - benzoquinone exhibited protection against huntington &# 39 ; s with an ec50 of less than about 50 nm . other compounds of the invention are tested using a screen similar to the one described . screening compounds of the invention in fibroblasts from leber &# 39 ; s hereditary optic neuropathy patients 2 , 3 , 5 - trimethyl - 6 -( 12 - hydroxy - 5 , 10 - dodecadiynyl )- 1 , 4 - benzoquinone was tested using a screen similar to the one described in example 1 , but substituting frda cells with leber &# 39 ; s hereditary optic neuropathy ( lhon ) cells obtained from the coriell cell repositories ( camden , n . j . ; repository number gm03858 ). the compound was tested for its ability to rescue human dermal fibroblasts from lhon patients from oxidative stress . 2 , 3 , 5 - trimethyl - 6 -( 12 - hydroxy - 5 , 10 - dodecadiynyl )- 1 , 4 - benzoquinone exhibited protection against lhon with an ec50 of less than about 100 nm . other compounds of the invention are tested using a screen similar to the one described . screening compounds of the invention in fibroblasts from parkinson &# 39 ; s disease patients 2 , 3 , 5 - trimethyl - 6 -( 12 - hydroxy - 5 , 10 - dodecadiynyl )- 1 , 4 - benzoquinone was tested using a screen similar to the one described in example 1 , but substituting frda cells with parkinson &# 39 ; s disease ( pd ) cells obtained from the coriell cell repositories ( camden , n . j . ; repository number ag20439 ). the compound was tested for its ability to rescue human dermal fibroblasts from parkinson &# 39 ; s disease patients from oxidative stress . 2 , 3 , 5 - trimethyl - 6 -( 12 - hydroxy - 5 , 10 - dodecadiynyl )- 1 , 4 - benzoquinone exhibited protection against parkinson &# 39 ; s disease with an ec50 of less than about 100 nm . other compounds of the invention are tested using a screen similar to the one described . screening compounds of the invention in fibroblasts from coq10 deficient patients compounds of the invention are tested using a screen similar to the one described in example 1 , but substituting frda cells with cells obtained from coq10 deficient patients harboring a coq2 mutation . the compounds are tested for their ability to rescue human dermal fibroblasts from coq10 deficient patients from oxidative stress . compounds of the invention are tested using a screen similar to the one described in example 1 , but substituting frda cells with cells obtained from patients having an oxidative stress disorder described herein ( e . g . merrf , melas , leigh disease , kss , alzheimer &# 39 ; s disease , als , a pervasive development disorder ( such as autism , rett &# 39 ; s ), stroke ). the compounds are tested for their ability to rescue human dermal fibroblasts from these patients from oxidative stress . a compound of the invention is presented in a capsule containing 300 mg of compound in a pharmaceutically acceptable carrier . a capsule is taken orally , once a day , preferably during breakfast or lunch . in case of very young children , the capsule is broken and its contents mixed with food . the disclosures of all publications , patents , patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety . although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding , it is apparent to those skilled in the art that certain minor changes and modifications will be practiced . therefore , the description and examples should not be construed as limiting the scope of the invention .
disclosed herein are compounds and methods of using such compounds for treating or suppressing oxidative stress disorders , including mitochondrial disorders , impaired energy processing disorders , neurodegenerative diseases and diseases of aging , or for modulating one or more energy biomarkers , normalizing one or more energy biomarkers , or enhancing one or more energy biomarkers , wherein the compound is a compound of formula i or formula ii : wherein : r 1 and r 2 are independently hydrogen , alkyl or — oalkyl ; or r 1 and r 2 together represent — ch ═ ch — ch ═ ch —; r 3 is alkyl ; x is — ch ═ ch — or — c ≡ c —; m is 1 - 10 ; n is 1 - 5 ; k is 1 - 3 , with the proviso that when k is an integer of 2 or 3 , n is independently 1 - 5 in each occurrence of the — x — n — group ; y is — or 4 , — cn , — cor 5 , — cr 5 , or — cn 2 ; r 4 and r 5 are independently selected from the group consisting of hydrogen , — alkyl , — haloalkyl , — c — alkyl , — c — haloalkyl , — c — nhalkyl , — c — nalkyl ) 2 , — c — nh 2 , and phenyl , wherein the phenyl group may optionally be substituted with a substituent selected from the group consisting of — alkyl , — o — alkyl , — haloalkyl , and halo ; each r 6 is independently hydrogen or — alkyl ; and m is — h , — c — r 7 or — co — r 7 , wherein r 7 is — alkyl or phenyl ; or a stereoisomer , mixture of stereoisomers , pharmaceutically acceptable salt , crystalline form , non - crystalline form , hydrate or solvate thereof .