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. Parkin is therefore required before mitophagy as it ubiquinates Mfn1/2, labelling it for proteasomal degradation. Proteomic studies identified additional OMM proteins as parkin 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 parkin. Miro breakdown produced a marked decrease in migration of compromised mitochondria along axons of mouse hippocampal neurons, reinforcing the importance of parkin in segregating defective mitochondria from their functioning counterparts and limiting the spatial spread of mitochondrial dysfunction, prior to autophagy. During mitophagy, parkin 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 parkin 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, parkin 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, parkin enhances survival and protects cells from stress-induced apoptosis. Upon cellular insult, parkin 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, parkin activates HOIP with greater potency than other LUBAC-associated factors HOIL-1 and sharpin, meaning that parkin mobilisation significantly enhances tolerance to moderate stressors. Parkin 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 parkin into SH-SY5Y neurons revealed that parkin directly binds to the p53 promoter via its RING1 domain. Conversely, parkin 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, parkin aids p53 in maintaining mitochondrial respiration