Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus

Alexandra MacColl Garfinkel, Nelli Mnatsakanyan, Jeet H. Patel, Andrea E. Wills, Amy Shteyman, Peter J.S. Smith, Kambiz N. Alavian, Elizabeth Ann Jonas, Mustafa K. Khokha

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An instructive role for metabolism in embryonic patterning is emerging, although a role for mitochondria is poorly defined. We demonstrate that mitochondrial oxidative metabolism establishes the embryonic patterning center, the Spemann-Mangold Organizer, via hypoxia-inducible factor 1α (Hif-1α) in Xenopus. Hypoxia or decoupling ATP production from oxygen consumption expands the Organizer by activating Hif-1α. In addition, oxygen consumption is 20% higher in the Organizer than in the ventral mesoderm, indicating an elevation in mitochondrial respiration. To reconcile increased mitochondrial respiration with activation of Hif-1α, we discovered that the “free” c-subunit ring of the F1Fo ATP synthase creates an inner mitochondrial membrane leak, which decouples ATP production from respiration at the Organizer, driving Hif-1α activation there. Overexpression of either the c-subunit or Hif-1α is sufficient to induce Organizer cell fates even when β-catenin is inhibited. We propose that mitochondrial leak metabolism could be a general mechanism for activating Hif-1α and Wnt signaling.

Original languageEnglish (US)
Pages (from-to)2597-2613.e4
JournalDevelopmental Cell
Issue number22
StatePublished - Nov 20 2023

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • Developmental Biology
  • Cell Biology

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