Mitophagy restricts BAX/BAK-independent, Parkin-mediated apoptosis

Abstract

Degradation of defective mitochondria is an essential process to maintain cellular homeostasis and it is strictly regulated by the ubiquitin-proteasome system (UPS) and lysosomal activities. Here, using genome-wide CRISPR and small interference RNA screens, we identified a critical contribution of the lysosomal system in controlling aberrant induction of apoptosis following mitochondrial damage. After treatment with mitochondrial toxins, activation of the PINK1-Parkin axis triggered a BAX- and BAK-independent process of cytochrome c release from mitochondria followed by APAF1 and caspase 9–dependent apoptosis. This phenomenon was mediated by UPS-dependent outer mitochondrial membrane (OMM) degradation and was reversed using proteasome inhibitors. We found that the subsequent recruitment of the autophagy machinery to the OMM protected cells from apoptosis, mediating the lysosomal degradation of dysfunctional mitochondria. Our results underscore a major role of the autophagy machinery in counteracting aberrant noncanonical apoptosis and identified autophagy receptors as key elements in the regulation of this process.

Efficient Prohibitin 2 exposure during mitophagy depends on Voltage-dependent anion-selective channel protein 1

“…During mitochondrial stress, there exists a continual competition between mitophagy and the possible release of Cytochrome c. Effective elimination of damaged mitochondria through mitophagy plays a crucial role in determining the outcome. A recent study has indeed shown that PINK-Parkin-induced proteasome-dependent rupture of the OMM can lead to the release of Cytochrome c when mitochondria are not adequately cleared through autophagic processes 38 . From our present findings, it appears that in situations where cellular autophagy mechanisms are active, the establishment of the VDAC1-PHB2 complex and the efficient exposure of PHB2 may have the potential to promote cell survival by facilitating mitophagy.…”

ALCAT1-mediated abnormal cardiolipin remodelling promotes mitochondrial injury in podocytes in diabetic kidney disease

“…It has also been proposed in the literature that following mitochondrial damage, cardiolipin is externalised to the outer mitochondrial membrane where it can be recognised by LC3 proteins thereby initiating mitochondrial autophagy to remove damaged mitochondria. In particular, oxidised cardiolipin can be specifically recognised by LC3A [ 47 ].The degradation of defective mitochondria is an essential process to maintain cellular homeostasis [ 48 ]. However, there is evidence of defective mitophagy in type 2 diabetic mice, such that damaged mitochondria cannot be cleared in a timely manner [ 49 ].…”

Mitochondrial quality control in human health and disease

“…In response to distinct stresses, PGAM5 dephosphorylates BCL-XL to inhibit apoptosis or FUNDC1 to enhance mitophagy by switching between dimeric and multimeric states [ 282 ]. Surprisingly, in the absence of mitophagy, PINK1/Parkin can promote cell apoptosis through a non-BAX pathway [ 283 ]. The ubiquitination effect of UPS on OMM promotes the release of cytochrome C, directly activates autophagy receptors, upregulates mitophagy, and inhibits apoptosis [ 283 ].…”

“…Surprisingly, in the absence of mitophagy, PINK1/Parkin can promote cell apoptosis through a non-BAX pathway [ 283 ]. The ubiquitination effect of UPS on OMM promotes the release of cytochrome C, directly activates autophagy receptors, upregulates mitophagy, and inhibits apoptosis [ 283 ].…”