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Dev Cell. 2019 Jun 3;49(5):748-763.e7. doi: 10.1016/j.devcel.2019.04.029. Epub 2019 May 16.

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

Author information

1
Departments of Orthopaedic Surgery, Medicine, and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
2
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Departments of Medicine and Cell Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
4
Departments of Orthopaedic Surgery, Medicine, and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. Electronic address: eschipan@med.umich.edu.

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.

KEYWORDS:

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

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