The ADP/ATP translocase drives mitophagy independent of nucleotide exchange

Atsushi Hoshino, Wei-jia Wang, Shogo Wada, Chris McDermott-Roe, Chantell S. Evans, Bridget Gosis, Michael P. Morley, Komal S. Rathi, Jian Li, Kristina Li, Steven Yang, Meagan J. McManus, Caitlyn Bowman, Prasanth Potluri, Michael Levin, Scott Damrauer, Douglas C. Wallace, Erika L. F. Holzbaur and Zoltan Arany ()
Additional contact information
Atsushi Hoshino: University of Pennsylvania
Wei-jia Wang: University of Pennsylvania
Shogo Wada: University of Pennsylvania
Chris McDermott-Roe: University of Pennsylvania
Chantell S. Evans: University of Pennsylvania
Bridget Gosis: University of Pennsylvania
Michael P. Morley: University of Pennsylvania
Komal S. Rathi: University of Pennsylvania
Jian Li: University of Pennsylvania
Kristina Li: University of Pennsylvania
Steven Yang: University of Pennsylvania
Meagan J. McManus: The Children’s Hospital of Philadelphia
Caitlyn Bowman: University of Pennsylvania
Prasanth Potluri: University of Pennsylvania
Michael Levin: University of Pennsylvania
Scott Damrauer: University of Pennsylvania
Douglas C. Wallace: University of Pennsylvania
Erika L. F. Holzbaur: University of Pennsylvania
Zoltan Arany: University of Pennsylvania

Nature, 2019, vol. 575, issue 7782, 375-379

Abstract: Abstract Mitochondrial homeostasis depends on mitophagy, the programmed degradation of mitochondria. Only a few proteins are known to participate in mitophagy. Here we develop a multidimensional CRISPR–Cas9 genetic screen, using multiple mitophagy reporter systems and pro-mitophagy triggers, and identify numerous components of parkin-dependent mitophagy1. Unexpectedly, we find that the adenine nucleotide translocator (ANT) complex is required for mitophagy in several cell types. Whereas pharmacological inhibition of ANT-mediated ADP/ATP exchange promotes mitophagy, genetic ablation of ANT paradoxically suppresses mitophagy. Notably, ANT promotes mitophagy independently of its nucleotide translocase catalytic activity. Instead, the ANT complex is required for inhibition of the presequence translocase TIM23, which leads to stabilization of PINK1, in response to bioenergetic collapse. ANT modulates TIM23 indirectly via interaction with TIM44, which regulates peptide import through TIM232. Mice that lack ANT1 show blunted mitophagy and consequent profound accumulation of aberrant mitochondria. Disease-causing human mutations in ANT1 abrogate binding to TIM44 and TIM23 and inhibit mitophagy. Together, our findings show that ANT is an essential and fundamental mediator of mitophagy in health and disease.

Date: 2019
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DOI: 10.1038/s41586-019-1667-4

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