SPATA33 functions as a mitophagy receptor in mammalian germline

Abstract

Mitophagy is an essential mechanism in maintaining cellular homeostasis, in which damaged and superfluous mitochondria are selectively degraded by the autophagy-lysosome pathway. Our recent study revealed that SPATA33 functions as a novel receptor for mitophagy in the priming of mitochondria for degradation in male germline cells. SPATA33 directly mediates the interaction of the outer mitochondrial membrane protein VDAC2 with the autophagy machinery component ATG16L1 during mitophagy. Upon starvation induction, SPATA33 can promote mitophagy as an autophagy receptor. Thus, SPATA33 confers cargo selectivity during mitophagy in germline cells. These findings provide new insights into selective autophagy and mitochondrial homeostasis.

Keywords: Autophagy; SPATA33; mammals; mitochondria; spermatogenesis.

Figure 1.

Mitophagy receptors. (A) SPATA33 functions as a mitophagy receptor. The C terminus of SPATA33 can interact with the mitochondrial outer membrane protein VDAC2. The N terminus of SPATA33 can bind to the WD40 region of ATG16L1. Upon starvation stress, damaged mitochondria are engulfed by autophagic membranes through SPATA33 linking VDAC2 and ATG16L1 to initiate mitophagy. (B) Ubiquitin-independent mitophagy. The autophagy receptors are outer mitochondrial membrane proteins, which have a common LIR/AIM motif that can bind to LC3B/Atg8 on the phagophore. (C) PINK-PRKN- or ubiquitin-dependent mitophagy. Mitophagy receptors are cytosolic proteins (CALCOCO2/NDP52 and OPTN), which bind ubiquitin. Accordingly, cytosolic receptors CALCOCO2/NDP52 and OPTN have both an AIM/LIR motif and a ubiquitin-binding domain. (D) The receptor SPATA33 mediates mitophagy via bridging between ATG16L1 and VDAC2, which is ATG16L1 dependent