PT - JOURNAL ARTICLE AU - Kahlon, Updip AU - Ricca, Francesco Dalla AU - Pillai, Saraswathi J. AU - Olivetta, Marine AU - Tharp, Kevin M. AU - Jao, Li-En AU - Dudin, Omaya AU - McDonald, Kent AU - Aydogan, Mustafa G. TI - A mitochondrial redox switch licenses the onset of morphogenesis in animals AID - 10.1101/2024.10.28.620733 DP - 2024 Jan 01 TA - bioRxiv PG - 2024.10.28.620733 4099 - http://biorxiv.org/content/early/2024/10/29/2024.10.28.620733.short 4100 - http://biorxiv.org/content/early/2024/10/29/2024.10.28.620733.full AB - Embryos undergo pre-gastrulation cleavage cycles to generate a critical cell mass before transitioning to morphogenesis. The molecular underpinnings of this transition have traditionally centered on zygotic chromatin remodeling and genome activation1,2, as their repression can prevent downstream processes of differentiation and organogenesis. Despite precedents that oxygen depletion can similarly suspend development in early embryos3–6, hinting at a pivotal role for oxygen metabolism in this transition, whether there is a bona fide chemical switch that licenses the onset of morphogenesis remains unknown. Here we discover that a mitochondrial oxidant acts as a metabolic switch to license the onset of animal morphogenesis. Concomitant with the instatement of mitochondrial membrane potential, we found a burst-like accumulation of mitochondrial superoxide (O2-) during fly blastoderm formation. In vivo chemistry experiments revealed that an electron leak from site IIIQo at ETC Complex III is responsible for O2- production. Importantly, depleting mitochondrial O2- fully mimics anoxic conditions and, like anoxia, induces suspended animation prior to morphogenesis, but not after. Specifically, H2O2, and not ONOO-, NO, or HO•, can single-handedly account for this mtROS-based response. We demonstrate that depleting mitochondrial O2- similarly prevents the onset of morphogenetic events in vertebrate embryos and ichthyosporea, close relatives of animals. We postulate that such redox-based metabolic licensing of morphogenesis is an ancient trait of holozoans that couples the availability of oxygen to development, conserved from early-diverging animal relatives to vertebrates.Competing Interest StatementThe authors have declared no competing interest.