bims-mitpro 2025-11-23 papers

Issue of 2025–11–23
two papers selected by
Andreas Kohler, Umeå University

EMBO J. 2025 Nov 20.

A unified mechanism for mitochondrial damage sensing in PINK1-Parkin-mediated mitophagy.

Julia A Thayer, Jennifer D Petersen, Xiaoping Huang, Luiza M Gruel Budet, James Hawrot, Daniel M Ramos, Shiori Sekine, Yan Li, Michael E Ward, Derek P Narendra.

Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed by the recessive Parkinson's disease genes PINK1 and Parkin. Whether the pathway senses diverse forms of mitochondrial damage via a common mechanism, however, remains uncertain. Here, using a novel Parkin reporter in genome-wide screens, we identified that diverse forms of mitochondrial damage converge on loss of mitochondrial membrane potential (MMP) to activate PINK1. Loss of MMP, but not the presequence translocase-associated import motor (PAM), blocked progression of PINK1 import through the translocase of the inner membrane (TIM23), causing it to remain bound to the translocase of the outer membrane (TOM). Ablation of TIM23 was sufficient to arrest PINK1 within TOM, irrespective of MMP. Meanwhile, TOM (including subunit TOMM5) was required for PINK1 retention on the mitochondrial surface. The energy state outside of the mitochondria further modulated the pathway by controlling the rate of new PINK1 synthesis. Together, our findings point to a convergent mechanism of PINK1-Parkin activation by mitochondrial damage: loss of MMP stalls PINK1 import during its transfer from TOM to TIM23.

Keywords: Autophagy; Glycolysis; Parkinson’s Disease; Unfolded Protein Response

DOI: https://doi.org/10.1038/s44318-025-00604-z

Mol Biol Cell. 2025 Nov 19. mbcE25050235

Kenny mediates the recruitment of the phagophore for ubiquitin-dependent mitophagy in Drosophila neurons.

Hubert Osei Acheampong, Emily Rozich, Zachary Haupt, Charlee Tokarz, Mousumee Khan, Zahraa A Ghosn, Ryan Insolera.

The maintenance of healthy mitochondria is essential to neuronal homeostasis. Mitophagy is a critical mechanism that degrades damaged mitochondria, and disruption of this process is associated with neurodegenerative disease. Previous work has shown that mammalian optineurin (OPTN), a gene mutated in familial forms of amyotrophic lateral sclerosis (ALS) and glaucoma, is an adaptor to recruit autophagy machinery to mitochondria for ubiquitin-dependent mitophagy in cultured cells. However, OPTN's role in neuronal mitophagy in vivo remains largely unknown. Here, we demonstrate the Drosophila autophagy adaptor gene Kenny, a homolog of OPTN, mediates the recruitment of the phagophore to mitochondria undergoing ubiquitin-dependent mitophagy. We find that Kenny colocalizes with ubiquitinated mitochondria targeted for autophagic degradation in larval motoneurons, and is concentrated on the mitochondrial surface in areas opposed to the phagophore. Removal of Kenny in conditions of induced mitophagy eliminates the recruitment of the phagophore to ubiquitinated mitochondria and decreases mitophagic flux. In basal conditions, loss of Kenny causes accumulation of ubiquitinated mitochondria in neurons, indicative of stalled mitophagy. These phenotypes were reproduced in Kenny mutants ablating the LC3-interacting region domain. Overall, this work establishes Kenny as a functional homolog of OPTN in flies, and a mediator of neuronal mitophagy in vivo.

DOI: https://doi.org/10.1091/mbc.E25-05-0235