Inhibition of apoptotic Bax translocation to the mitochondria is a central function of parkin

Abstract

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, affecting 1–3% of the population over 65. Mutations in the ubiquitin E3 ligase parkin are the most common cause of autosomal recessive PD. The parkin protein possesses potent cell-protective properties and has been mechanistically linked to both the regulation of apoptosis and the turnover of damaged mitochondria. Here, we explored these two functions of parkin and the relative scale of these processes in various cell types. While biochemical analyses and subcellular fractionation were sufficient to observe robust parkin-dependent mitophagy in immortalized cells, higher resolution techniques appear to be required for primary culture systems. These approaches, however, did affirm a critical role for parkin in the regulation of apoptosis in primary cultured neurons and all other cells studied. Our prior work demonstrated that parkin-dependent ubiquitination of endogenous Bax inhibits its mitochondrial translocation and can account for the anti-apoptotic effects of parkin. Having found a central role for parkin in the regulation of apoptosis, we further investigated the parkin-Bax interaction. We observed that the BH3 domain of Bax is critical for its recognition by parkin, and identified two lysines that are crucial for parkin-dependent regulation of Bax translocation. Last, a disease-linked mutation in parkin failed to influence Bax translocation to mitochondria after apoptotic stress. Taken together, our data suggest that regulation of apoptosis by the inhibition of Bax translocation is a prevalent physiological function of parkin regardless of the kind of cell stress, preventing overt cell death and supporting cell viability during mitochondrial injury and repair.

Mitophagy acts as a safeguard mechanism against human vascular smooth muscle cell apoptosis induced by atherogenic lipids

“…Our hypotheses are strengthened by recent reports showing that primary cultured neurons from Parkin knock-out mice accumulated greater levels of Bax at the mitochondria than wild type neurons after apoptotic stimulation [39]. The reduced Bax levels observed in human VSMC-overexpressing Parkin, seems not involved effects on transcription, but rather required Parkin-dependent ubiquitination of Bax and proteasomal degradation [30,40]. Therefore, we cannot exclude the coexistence and cooperation of both Parkin-dependent www.impactjournals.com/oncotarget regulations of mitochondrial clearance and apoptotic pathways within the same cells.…”

Neuropathic alterations of the myenteric plexus neurons following subacute intraperitoneal administration of salsolinol

“…Some experiments showed that Bax is an important regulator of apoptotic neurodegeneration and that Bax plays a pivotal role in the destruction of dopamine-producing neurons in a mouse model of PD [39]. In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-injected mice Bax expression levels were increased in regions specifically affected by the neurodegeneration processes [39,40]. So far, Naoi et al demonstrated the cell death caused by salsolinol in human dopaminergic neuroblastoma SH-SY5Y cells to be apoptotic [18].…”

Parkin and PINK1 functions in oxidative stress and neurodegeneration

“…Together, this highlights the likely possibility that PINK1 and Parkin have both dependent and independent functions and the possibility that some of these functions are distinct from mitochondrial autophagy. Additional examples of independent and distinct functions include Parkin regulation of mitochondrial cytochrome c release, BAX translocation to mitochondria, and apoptosis (Berger et al 2009; Johnson et al 2012a; Johnson et al 2012b; Charan et al 2014), and PINK1 regulation of neuronal dendritic morphology (Dagda et al 2014). …”