A naturally occurring mutation in ATP synthase subunit c is associated with increased damage following hypoxia/reoxygenation in STEMI patients

Cell Rep. 2021 Apr 13;35(2):108983. doi: 10.1016/j.celrep.2021.108983.


Preclinical models of ischemia/reperfusion injury (RI) demonstrate the deleterious effects of permeability transition pore complex (PTPC) opening in the first minutes upon revascularization of the occluded vessel. The ATP synthase c subunit (Csub) influences PTPC activity in cells, thus impacting tissue injury. A conserved glycine-rich domain in Csub is classified as critical because, when mutated, it modifies ATP synthase properties, protein interaction with the mitochondrial calcium (Ca2+) uniporter complex, and the conductance of the PTPC. Here, we document the role of a naturally occurring mutation in the Csub-encoding ATP5G1 gene at the G87 position found in two ST-segment elevation myocardial infarction (STEMI) patients and how PTPC opening is related to RI in patients affected by the same disease. We report a link between the expression of ATP5G1G87E and the response to hypoxia/reoxygenation of human cardiomyocytes, which worsen when compared to those expressing the wild-type protein, and a positive correlation between PTPC and RI.

Keywords: ATP synthase; PTP; STEMI patients; cardiovascular diseases; glycine-rich domain; ischemia; mitochondria; reperfusion injury; subunit c.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Base Sequence
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Exons
  • Female
  • Gene Expression
  • Humans
  • Hypoxia / genetics*
  • Hypoxia / metabolism
  • Hypoxia / pathology
  • Introns
  • Male
  • Middle Aged
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitochondrial Permeability Transition Pore / metabolism*
  • Mitochondrial Proton-Translocating ATPases / deficiency
  • Mitochondrial Proton-Translocating ATPases / genetics*
  • Mutation
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Oxygen / adverse effects
  • Prospective Studies
  • Reperfusion Injury / genetics
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • ST Elevation Myocardial Infarction / genetics*
  • ST Elevation Myocardial Infarction / metabolism
  • ST Elevation Myocardial Infarction / pathology


  • Calcium Channels
  • Mitochondrial Permeability Transition Pore
  • mitochondrial calcium uniporter
  • ATP5F1A protein, human
  • ATP5MC1 protein, human
  • Mitochondrial Proton-Translocating ATPases
  • Oxygen