PINK1 is a mitochondrial serine/threonine kinase that acts as a sensor of mitochondrial damage []. It phosphorylates ubiquitin (Ub) and the Ub-like domain (UBL) of the E3 Ub ligase parkin at Ser65. The phosphorylation of Ub and the parkin UBL facilitates the transition from the autoinhibition state to the catalytically active state in parkin []. Upon mitochondrial damage, PINK1 accumulates on the outer mitochondrial membrane (OMM), where it may recruit and activate Parkin []. PINK1 has also been shown to phosphorylate Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner []. PINK1 contains an N-terminal mitochondrial targeting sequence (MTS), a transmembrane domain (TM), a highly conserved serine/threonine kinase domain, and a C-terminal auto-regulatory domain. Mutations of the PINK1 and Parkin genes have been linked to familial Parkinson's disease (PD) [].
Synphilin-1 interacts with and is ubiquitylated by the E3 ubiquitin ligase SIAH. It also interacs with PINK1 and is recruited to the mitochondria where promotes PINK1-dependent mitophagy. Synphilin-1, SIAH-1 and PINK1 seem to constitute a new mitophagy pathway [].Synphilin-1 is an alpha-synuclein-interacting protein that promotes the formation of inclusion bodies []. Alternative splicing gives rise to at least eight synphilin-1 isoforms []. Among them, synphilin-1A is an aggregation-prone protein that causes neuronal toxicity []. Synphilin-1A has been linked to Parkinson's disease [].
