IDH3 mediates apoptosis of alveolar epithelial cells type 2 due to mitochondrial Ca 2+ uptake during hypocapnia

Cell Death Dis. 2017 Aug 24;8(8):e3005. doi: 10.1038/cddis.2017.403.

Abstract

In adult respiratory distress syndrome (ARDS) pulmonary perfusion failure increases physiologic dead-space (VD/VT) correlating with mortality. High VD/VT results in alveolar hypocapnia, which has been demonstrated to cause edema formation, atelectasis, and surfactant depletion, evoked, at least in part, by apoptosis of alveolar epithelial cells (AEC). However, the mechanism underlying the hypocapnia-induced AEC apoptosis is unknown. Here, using fluorescent live-cell imaging of cultured AEC type 2 we could show that in terms of CO2 sensing the tricarboxylic acid cycle enzyme isocitrate dehydrogenase (IDH) 3 seems to be an important player because hypocapnia resulted independently from pH in an elevation of IDH3 activity and subsequently in an increase of NADH, the substrate of the respiratory chain. As a consequence, the mitochondrial transmembrane potential (ΔΨ) rose causing a Ca2+ shift from cytosol into mitochondria, whereas the IDH3 knockdown inhibited these responses. Furthermore, the hypocapnia-induced mitochondrial Ca2+ uptake resulted in reactive oxygen species (ROS) production, and both the mitochondrial Ca2+ uptake and ROS production induced apoptosis. Accordingly, we provide evidence that in AEC type 2 hypocapnia induces elevation of IDH3 activity leading to apoptosis. This finding might give new insight into the pathogenesis of ARDS and may help to develop novel strategies to reduce tissue injury in ARDS.

MeSH terms

  • A549 Cells
  • Alveolar Epithelial Cells / metabolism*
  • Alveolar Epithelial Cells / pathology
  • Animals
  • Apoptosis / physiology
  • Calcium / metabolism*
  • Humans
  • Hypocapnia / enzymology
  • Hypocapnia / metabolism*
  • Hypocapnia / pathology
  • Isocitrate Dehydrogenase / metabolism*
  • Male
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Respiratory Distress Syndrome / enzymology
  • Respiratory Distress Syndrome / metabolism*
  • Respiratory Distress Syndrome / pathology

Substances

  • Reactive Oxygen Species
  • Isocitrate Dehydrogenase
  • Calcium