Mitochondrial dysfunction in survivors of acute lymphoblastic leukemia
Childhood acute lymphoblastic leukemia (cALL) is the most prevalent form of paediatric cancer. Fortunately, advances in treatment have allowed for approximately 90% of those diagnosed with cALL to survive at least 5 years post treatments. However, almost two thirds of cALL survivors present at least one considerable complication due to long-term secondary effects following aggressive treatments. The metabolic syndrome (metS) and its components are present among this group of paediatric cancer survivors and are risk factors of cardiovascular diseases. Surprisingly, little information is available on mitochondrial status in paediatric cancer survivors even if these organelles display central roles in metabolic processes and their dysfunction has been connected to the development of cardiometabolic complications. The objective of this study is to determine if the appearance of cardiometabolic complications in cALL survivors is associated with alterations in the composition and functions of key mitochondrial proteins leading to dysfunctional mitochondria. Methods. We evaluated the cardiometabolic profile of a group of 52 cALL survivors classing them as either metabolically healthy or metabolically unhealthy. Mitochondria from white blood cells were isolated, assessed in several of their characteristic functions, and analyzed by the proteomic approach. Lipid peroxidation was measured and the expression of functional proteins was examined by western blot analysis and commercial ELISA kits. Results. Our findings demonstrated differences in protein expression among controls and the cALL survivor group. cALL survivors expressed lower antioxidant superoxide dismutase along with increased oxidative stress as reflected by raised malondialdehyde levels. Increased cytochrome c indicated elevated apoptosis whereas decreased expression of PGC1-α transcription factor revealed mitochondrial biogenesis reduction. Proteomic analysis identified 957 proteins within our groups. Furthermore we could evidence alterations among groups in the regulation of mitochondrial proteins including those related to signalling pathways, inflammation, apoptosis, energy production, β-oxidation, oxidoreduction, and protein transport and metabolism. Conclusion. Our proteomic and functional analysis among cALL survivors reveal differences in the presence, concentration and function of mitochondrial proteins compared to controls. These results may indicate an association between dysfunctional mitochondria and cardiometabolic complications among cALL survivors. Further studies are necessary to confirm whether mitochondrial dysfunctions are responsible for the development of cardiometabolic complications in this population.
Hypertension Acute Lymphoblastic Leukemia Cancer Survivors Paediatric Mitochondria Cardiometabolic Metabolic Syndrome Obesity Dyslipidemia Insulin Resistance