Parkin and PINK1 signaling in PD. (A) Loss of parkin E3 ligase activity via PD-associated mutations or PTM results in the accumulation of its substrates. Accrual of the amino-acyl tRNA cofactor AIMP2 results in poly(ADP-ribose) polymerase-1 (PARP1)–dependent neuron death. Buildup of PARIS/ZNF746, a transcription inhibitor, prevents mitochondrial biogenesis by repressing the expression of PGC-1α, the master mitochondrial biogenesis regulator. (B) PINK1 is a serine/threonine kinase that phosphorylates (depicted by a red PD) both ubiquitin and parkin at S65, allowing parkin to be recruited to damaged mitochondria. This is followed by the parkin-mediated polyubiquitination of OMM proteins, culminating in the clearance of damaged mitochondria via mitophagy. (C) PINK1/parkin signaling maintains a balance between mitochondrial fission and fusion. (D) Finally, PINK1/parkin inhibit mitochondrial transport by phosphorylating and ubiquitinating the protein Miro, causing mitochondrial detachment from the microtubule. Ub, ubiquitin.