A mitochondrial redox switch licenses the onset of morphogenesis in animals

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 activation 1,2 , as their repression can prevent downstream processes of differentiation and organogenesis. Despite precedents that oxygen depletion can similarly suspend development in early embryos 3–6 , 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 (O 2 - ) during fly blastoderm formation. In vivo chemistry experiments revealed that an electron leak from site III Qo at ETC Complex III is responsible for O 2 - production. Importantly, depleting mitochondrial O 2 - fully mimics anoxic conditions and, like anoxia, induces suspended animation prior to morphogenesis, but not after. Specifically, H 2 O 2 , and not ONOO - , NO, or HO•, can single-handedly account for this mtROS-based response. We demonstrate that depleting mitochondrial O 2 - 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.