Suppressing Mitochondrial Respiration Is Critical for Hypoxia Tolerance in the Fetal Growth Plate

Qing Yao, Mohd Parvez Khan, Christophe Merceron, Edward L. LaGory, Zachary Tata, Laura Mangiavini, Jiarui Hu, Krishna Vemulapalli, Navdeep S. Chandel, Amato J. Giaccia, Ernestina Schipani*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Oxygen (O2) is both an indispensable metabolic substrate and a regulatory signal that controls the activity of Hypoxia-Inducible Factor 1α (Hif1a), a mediator of the cellular adaptation to low O2 tension (hypoxia). Hypoxic cells require Hif1a to survive. Additionally, Hif1a is an inhibitor of mitochondrial respiration. Hence, we hypothesized that enhancing mitochondrial respiration is detrimental to the survival of hypoxic cells in vivo. We tested this hypothesis in the fetal growth plate, which is hypoxic. Our findings show that mitochondrial respiration is dispensable for survival of growth plate chondrocytes. Furthermore, its impairment prevents the extreme hypoxia and the massive chondrocyte death observed in growth plates lacking Hif1a. Consequently, augmenting mitochondrial respiration affects the survival of hypoxic chondrocytes by, at least in part, increasing intracellular hypoxia. We thus propose that partial suppression of mitochondrial respiration is crucial during development to protect the tissues that are physiologically hypoxic from lethal intracellular anoxia. The fetal growth plate is a hypoxic structure that gives rise to most of the skeleton. It is formed by cells known as chondrocytes. Yao et al. now show that impairment of mitochondrial respiration and, thus, oxygen consumption are crucial for the survival of hypoxic chondrocytes during fetal development.

Original languageEnglish (US)
Pages (from-to)748-763.e7
JournalDevelopmental Cell
Volume49
Issue number5
DOIs
StatePublished - Jun 3 2019

Keywords

  • HIF
  • TFAM
  • cell death
  • chondrocyte
  • fetal development
  • glycolysis
  • growth plate
  • hypoxia
  • mitochondria
  • mitochondrial respiration

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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