There is increasing awareness that nutrient uptake and utilization play key roles in determining cell fate specification during development. Mitochondria integrate these nutrient inputs translating them into energy and signals. Mitochondrial DNA mutations that disrupt mitochondrial activity cause disease and disability. How they impact the role of nutrients in developmental decision making remains poorly understood. Here we find that in human pluripotent stem cells, mutations in mtND6, a component of Complex I of the electron transport chain, induce a switch in the uptake of nutrients that sustain proliferation, from glucose to fatty acids. Importantly, this switch leads to an enhanced response to BMP4, the signal that directs germ layer self-organization in gastruloids, causing disrupted patterning in these models. These results demonstrate that by determining the mode of nutrient uptake, mitochondrial activity fine tunes the cells' signalling output to direct proper embryo organization, and that this process is compromised by disease causing mutations.
Bian, S., Marcheluk, M. M., Lima, A. R., Li, S., Price, C. J., Azuara, V. A., Barbaric, I., Rodriguez, T. A.
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