Mitophagy<unk> plays a crucial role in mitophagy and clearance of reactive oxygen species. Mitophagy is the elimination of damaged mitochondria in autophagosomes, and is dependent on a positive feedback cycle involving synergistic action of<unk> and PINK1. Following severe cellular insult, rundown of mitochondrial membrane potential prevents import of PINK1 into the mitochondrial matrix and causes it to aggregate on the outer mitochondrial membrane (OMM).<unk> is recruited to mitochondria following depolarisation and phosphorylated by PINK1, which simultaneously phosphorylates Ub pre-conjugated to mitochondrial membrane proteins. PINK1 and Ub phosphorylation facilitate<unk> activation and further assembly of mono- and poly-Ub chains. Considering the proximity of these chains to PINK1, further phosphorylation of Ub at Ser65 is likely, potentiating<unk> mobilisation and substrate ubiquitination in a self-reinforcing cycle.<unk> substrates include mitofusins Mfn1 and Mfn2, which are large GTPases that promote mitochondria fusion into dynamic, tubular complexes that maximise efficiency of oxidative phosphorylation. However, upon mitochondrial damage, degradation of fusion proteins is necessary to separate them from the network via mitochondrial fission and prevent the corruption of healthy mitochondria.<unk> is therefore required before mitophagy as it ubiquinates Mfn1/2, labelling it for proteasomal degradation. Proteomic studies identified additional OMM proteins as<unk> substrates, including fission protein FIS, its adaptor TBC1D15 and translocase TOMM20 and TOMM70 that facilitate movement of proteins such as PINK1 across OMM. Miro (or RHOT1/RHOT2) is an OMM protein critical for axonal transport, and may be ubiquitinated and targeted towards proteasomal degradation by<unk>  Miro breakdown produced a marked decrease in migration of compromised mitochondria along axons of mouse hippocampal neurons, reinforcing the importance of<unk> in segregating defective mitochondria from their functioning counterparts and limiting the spatial spread of mitochondrial dysfunction, prior to autophagy. During mitophagy,<unk> targets VDAC1, a voltage-gated anion channel that undergoes a conformational change upon mitochondrial membrane depolarisation, exposing a cytosolic domain for ubiquitination. Silencing of VDAC1 expression in HeLa cells significantly reduced<unk> recruitment to depolarised mitochondria and their subsequent clearance, highlighting the critical role of VDAC1 as a selective marker of mitochondrial damage and instigator of mitophagy. Following Ub conjugation,<unk> recruits autophagy receptors such as p62, TAX1BP1 and CALCOCO2, facilitating assembly of autophagosomes that digest defective mitochondria. Cell survival Through activation of NF-κB signalling,<unk> enhances survival and protects cells from stress-induced apoptosis. Upon cellular insult,<unk> activates the catalytic HOIP subunit of another E3 ligase LUBAC. HOIP triggers assembly of linear Ub polymers on NF-κB essential modulator (NEMO), potentiating transcription of mitochondrial GTPase OPA1. Increased OPA1 translation maintains cristae structure and reduces cytochrome C release from mitochondria, inhibiting caspase-mediated apoptosis. Importantly,<unk> activates HOIP with greater potency than other LUBAC-associated factors HOIL-1 and sharpin, meaning that<unk> mobilisation significantly enhances tolerance to moderate stressors.<unk> possesses DNA binding affinity and produces a dose-dependent reduction in transcription and activity of pro-apoptotic factor p53. Transfection of p53 promoter with truncated versions of<unk> into SH-SY5Y neurons revealed that<unk> directly binds to the p53 promoter via its RING1 domain. Conversely,<unk> may be a transcriptional target of p53 in H460 lung cells, where it mediates the tumour suppressor action of p53. Considering its role in mitochondrial homeostasis,<unk> aids p53 in maintaining mitochondrial respiration while limiting glucose uptake and lactate production, thus preventing onset of the Warburg effect during tumourigenesis.<unk> further elevates cytosolic glutathione levels and protects against oxidative stress, characterising it as a critical tumour suppressor with anti-glycolytic and antioxidant capabilities.
Parkin 
Peripherin
CEPP
Tetraspanin
Dystrophin
Alpha-synuclein
Huntingtin-interacting protein 1
MSin3 interaction domain