2. Academic Validation
  3. The ADP/ATP translocase drives mitophagy independent of nucleotide exchange

The ADP/ATP translocase drives mitophagy independent of nucleotide exchange

  • Nature. 2019 Nov;575(7782):375-379. doi: 10.1038/s41586-019-1667-4.
Atsushi Hoshino  # 1 2,  Wei-Jia Wang  # 1 3,  Shogo Wada 1,  Chris McDermott-Roe 1,  Chantell S Evans 4,  Bridget Gosis 1,  Michael P Morley 1,  Komal S Rathi 1 5,  Jian Li 1,  Kristina Li 1,  Steven Yang 1,  Meagan J McManus 6 7,  Caitlyn Bowman 1,  Prasanth Potluri 7,  Michael Levin 1,  Scott Damrauer 8,  Douglas C Wallace 7,  Erika L F Holzbaur 4,  Zoltan Arany 9
Affiliations

Affiliations

  • 1 Department of Medicine, Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 2 Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
  • 3 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
  • 4 Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 5 Department of Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 6 Department of Anesthesiology & Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 7 Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, and the Division of Human Genetics and Metabolism, Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA.
  • 8 Department of Surgery, Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 9 Department of Medicine, Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • # Contributed equally.
PMID: 31618756 DOI: 10.1038/s41586-019-1667-4
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.

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