Editors' ChoiceDevelopmental Biology

Mitochondrial respiration not required

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Science Signaling  11 Jun 2019:
Vol. 12, Issue 585, eaay2985
DOI: 10.1126/scisignal.aay2985

Chondrocytes survive constitutive hypoxia by suppressing mitochondrial respiration.

Cartilage is inherently hypoxic because it is avascular. The transcription factor hypoxia-inducible factor (HIF) is critical for the survival and function of chondrocytes in both articular and growth plate cartilage because it stimulates the expression of genes that inhibit mitochondrial respiration and promote anaerobic respiration under conditions of low oxygen. Yao et al. deleted Tfam, a transcription factor that promotes the expression of mitochondrial genes encoding components of the electron transport chain, specifically in mouse limb bud mesenchyme, the tissue that gives rise to growth plate chondrocytes. Tfam knockout reduced mitochondrial DNA content and respiration in chondrocytes as expected, but it did not affect chondrocyte proliferation, cell death, or growth plate morphology, indicating that mitochondrial respiration is not necessary for cartilage development. Furthermore, Tfam knockout eliminated hypoxia in the growth plate, a key feature of this tissue in wild-type embryos. The loss of Tfam rescued the growth plate defects and widespread chondrocyte death caused by the loss of Hif1α alone or with Hif2α. Experiments measuring metabolic parameters in chondrocytes isolated from mutant and control mice demonstrated that loss of Hif1α or Tfam did not affect the ability of cells to generate energy under normoxic or hypoxic conditions, that loss of Tfam restored hypoxia-induced glycolysis in Hif1α-deficient cells, and that death of Hif1α-deficient chondrocytes was caused by increased intracellular hypoxia rather than caspase-mediated apoptosis. Thus, chondrocytes manage constitutive hypoxia by suppressing mitochondrial respiration, and Hif1α is dispensable in this context if mitochondrial respiration is suppressed by other means. Commentary by Long highlights some of the questions about chondrocyte metabolism raised by these findings.

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