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Dev Cell 2023 Nov 20;5822:2597-2613.e4. doi: 10.1016/j.devcel.2023.08.015.
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Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus.

MacColl Garfinkel A , Mnatsakanyan N , Patel JH , Wills AE , Shteyman A , Smith PJS , Alavian KN , Jonas EA , Khokha MK .

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.

PubMed ID: 37673063
PMC ID: PMC10840693
Article link: Dev Cell
Grant support: [+]

Species referenced: Xenopus tropicalis Xenopus laevis
Genes referenced: chrd gsc hk2 lrpprc slc2a1 surf1 tbxt ventx2.2
GO keywords: mitochondrial proton-transporting ATP synthase complex [+]
Antibodies: Ctnnb1 Ab25 Gapdh Ab5 hif1a Ab1 lrpprc Ab1
Morpholinos: ctnnb1 MO2 hif1a MO5 lrpprc MO1

Article Images: [+] show captions
References [+] :
Alavian, An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. 2014, Pubmed