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Cell death and differentiation
09, 2022;29 (9): 1874-1887.

Mitochondrial ATP synthase c-subunit leak channel triggers cell death upon loss of its F subcomplex.

Nelli Mnatsakanyan, Han-A Park, Jing Wu, Xiang He, Marc C Llaguno, Maria Latta, Paige Miranda, Besnik Murtishi, Morven Graham, Joachim Weber, Richard J Levy, Evgeny V Pavlov, Elizabeth A Jonas
Author Information
  1. Nelli Mnatsakanyan: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA. nmnatsakanyan@pennstatehealth.psu.edu. ORCID
  2. Han-A Park: Department of Human Nutrition & Hospitality Management, University of Alabama, Tuscaloosa, AL, USA.
  3. Jing Wu: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
  4. Xiang He: Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China.
  5. Marc C Llaguno: Center for Cellular and Molecular Imaging, Yale University, New Haven, CT, USA.
  6. Maria Latta: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
  7. Paige Miranda: Center for Neural Science, New York University, New York, NY, USA.
  8. Besnik Murtishi: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
  9. Morven Graham: Center for Cellular and Molecular Imaging, Yale University, New Haven, CT, USA. ORCID
  10. Joachim Weber: Texas Tech University, Department of Chemistry and Biochemistry, Lubbock, TX, USA.
  11. Richard J Levy: Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA.
  12. Evgeny V Pavlov: Department of Basic Sciences, New York University, New York, NY, USA.
  13. Elizabeth A Jonas: Section of Endocrinology, Department of Internal Medicine, Yale University, PO Box 208020, New Haven, CT, USA. elizabeth.jonas@yale.edu. ORCID
PMID: 35322203 DOI: 10.1038/s41418-022-00972-7

Abstract

Mitochondrial ATP synthase is vital not only for cellular energy production but also for energy dissipation and cell death. ATP synthase c-ring was suggested to house the leak channel of mitochondrial permeability transition (mPT), which activates during excitotoxic ischemic insult. In this present study, we purified human c-ring from both eukaryotic and prokaryotic hosts to biophysically characterize its channel activity. We show that purified c-ring forms a large multi-conductance, voltage-gated ion channel that is inhibited by the addition of ATP synthase F subcomplex. In contrast, dissociation of F from F occurs during excitotoxic neuronal death suggesting that the F constitutes the gate of the channel. mPT is known to dissipate the osmotic gradient across the inner membrane during cell death. We show that ATP synthase c-subunit knock down (KD) prevents the osmotic change in response to high calcium and eliminates large conductance, Ca and CsA sensitive channel activity of mPT. These findings elucidate the gating mechanism of the ATP synthase c-subunit leak channel (ACLC) and suggest how ACLC opening is regulated by cell stress in a CypD-dependent manner.

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Grants

  1. K01 AG054734/NIA NIH HHS
  2. RF1 AG072484/NIA NIH HHS
  3. R01 GM115570/NIGMS NIH HHS
  4. P30 DK045735/NIDDK NIH HHS
  5. R01 NS045876/NINDS NIH HHS
  6. R37 NS045876/NINDS NIH HHS

MeSH Term

Adenosine Triphosphate
Cell Death
Humans
Mitochondrial Membrane Transport Proteins
Mitochondrial Permeability Transition Pore
Mitochondrial Proton-Translocating ATPases
Proton-Translocating ATPases

Chemicals

Mitochondrial Membrane Transport Proteins
Mitochondrial Permeability Transition Pore
Adenosine Triphosphate
Mitochondrial Proton-Translocating ATPases
Proton-Translocating ATPases
Journal Article Research Support, N.I.H., Extramural
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