The PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway

Abstract

PTEN-induced putative kinase 1 (PINK1) and parkin are mutated in familial forms of Parkinson's disease and are important in promoting the mitophagy of damaged mitochondria. In this study, we showed that synphilin-1 interacted with PINK1 and was recruited to the mitochondria. Once in the mitochondria, it promoted PINK1-dependent mitophagy, as revealed by Atg5 knockdown experiments and the recruitment of LC3 and Lamp1 to the mitochondria. PINK1-synphilin-1 mitophagy did not depend on PINK1-mediated phosphorylation of synphilin-1 and occurred in the absence of parkin. Synphilin-1 itself caused depolarization of the mitochondria and increased the amount of uncleaved PINK1 at the organelle. Furthermore, synphilin-1 recruited seven in absentia homolog (SIAH)-1 to the mitochondria where it promoted mitochondrial protein ubiquitination and subsequent mitophagy. Mitophagy via this pathway was impaired by synphilin-1 knockdown or by the use of a synphilin-1 mutant that is unable to recruit SIAH-1 to the mitochondria. Likewise, knockdown of SIAH-1 or the use of a catalytically inactive SIAH-1 mutant abrogated mitophagy. PINK1 disease mutants failed to recruit synphilin-1 and did not activate mitophagy, indicating that PINK1-synphilin-1-SIAH-1 represents a new parkin-independent mitophagy pathway. Drugs that activate this pathway will provide a novel strategy to promote the clearance of damaged mitochondria in Parkinson's disease.

How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

“…Support for this possibility came from a recent study demonstrating the ubiquitylation of MOM proteins combined with a translocation of synphilin-1 to mitochondria in a Pink1-dependent, yet Parkin-independent manner (Szargel et al, 2016). A physical interaction of Pink1 to synphylin-1 was additionally shown.…”

“…Despite the absence of Parkin in the system, ubiquitylation of MOM proteins was found to depend on seven in absentia homolog 1 (SIAH-1), an E3-ubiquitin ligase. This pathway is in principle reminiscent to the Pink1/Parkin system, yet SIAH-1 does not appear to promote proteasomal degradation of MOM proteins (Szargel et al, 2016) which is observed during Parkin-mediated mitophagy (Yoshii et al, 2011).…”

Neuronal Mitophagy in Neurodegenerative Diseases

“…Recent work by Szargel et al (2016) showed that, in the absence of Parkin, other E3 UB ligases such as SIAH-1 could catalyze the polyubiquitination of OMM proteins. PINK1 is still necessary for the phosphorylation of UB, however, suggesting that although the P-UB chains on the mitochondrial surface are the signal for mitophagy receptors, parkin is not essential for this process (Szargel et al, 2016).…”

“…PINK1 is still necessary for the phosphorylation of UB, however, suggesting that although the P-UB chains on the mitochondrial surface are the signal for mitophagy receptors, parkin is not essential for this process (Szargel et al, 2016). …”

Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

“…Taken together with its role in Mfn1 ubiquitination, this implies that FBXO7 may interact with other proteins to initiate PINK1-dependent mitophagy, and that targeting FBXO7 expression could potentially circumvent parkin deficiencies. Additionally, a recent study found that PINK1 will recruit synphilin-1 to the mitochondria, thereby inducing mitochondrial depolarization (Szargel et al, 2016). After depolarization, Synphilin-1 was shown to recruit SIAH-1, an E3 ubiquitin ligase, to the mitochondria where it initiates mitophagy.…”