Roy, M., Nandy, S., Marchesan, E., Banerjee, C., Mondal, R., Caicci, F., Ziviani, E., Chakraborty, J. (2025). Efficient PHB2 (prohibitin 2) exposure during mitophagy depends on VDAC1 (voltage dependent anion channel 1).  Autophagy 21(4): 897--909.

FBrf0261944

Research paper

Exposure of inner mitochondrial membrane resident protein PHB2 (prohibitin 2) during autophagic removal of depolarized mitochondria (mitophagy) depends on the ubiquitin-proteasome system. This uncovering facilitates the PHB2 interaction with phagophore membrane-associated protein MAP1LC3/LC3. It is unclear whether PHB2 is exposed randomly at mitochondrial rupture sites. Prior knowledge and initial screening indicated that VDAC1 (voltage dependent anion channel 1) might play a role in this phenomenon. Through in vitro biochemical assays and imaging, we have found that VDAC1-PHB2 interaction increases during mitochondrial depolarization. Subsequently, this interaction enhances the efficiency of PHB2 exposure and mitophagy. To investigate the relevance in vivo, we utilized porin (equivalent to VDAC1) knockout Drosophila line. Our findings demonstrate that during mitochondrial stress, porin is essential for Phb2 exposure, Phb2-Atg8 interaction and mitophagy. This study highlights that VDAC1 predominantly synchronizes efficient PHB2 exposure through mitochondrial rupture sites during mitophagy. These findings may provide insights to understand progressive neurodegeneration.

PMC12506749 (PMC) (EuropePMC)