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bioRxiv · 10.1101/2022.06.01.494337

Opa1 and Drp1 reciprocally regulate cristae morphology, ETC function, and NAD+ regeneration in KRas-mutant lung adenocarcinoma

Sessions, D. T.·Kim, K.-B.·Kashatus, J. A.·Churchill, N.·Park, K.-S.·Mayo, M. W.·Sesaki, H.·Kashatus, D. F.
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Abstract

Oncogenic KRas activates mitochondrial fission through Erk-mediated phosphorylation of the mitochondrial fission GTPase Drp1. Drp1 deletion inhibits tumorigenesis of KRas-driven pancreatic cancer, but the role of mitochondrial dynamics in other Ras-driven malignancies is poorly defined. Here we demonstrate that in vitro and in vivo growth of KRas-driven lung adenocarcinoma is unaffected by deletion of Drp1, but inhibited by deletion of Opa1, the GTPase that regulates inner membrane fusion and promotes proper cristae morphology. Mechanistically, Opa1 knockout induces loss of electron transport chain (ETC) complex I assembly and activity that inhibits tumor cell proliferation through loss of NAD+ regeneration. Simultaneous inactivation of Drp1 and Opa1 restores cristae morphology, complex I activity and cell proliferation indicating that mitochondrial fission activity drives ETC dysfunction induced by Opa1 knockout. Our results support a model in which mitochondrial fission events disrupt cristae structure and tumor cells with hyperactive fission activity require Opa1 activity to maintain ETC function.

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Sessions, D. T., Kim, K.-B., Kashatus, J. A., Churchill, N., Park, K.-S., Mayo, M. W., Sesaki, H., Kashatus, D. F.. 2022-06-01. Opa1 and Drp1 reciprocally regulate cristae morphology, ETC function, and NAD+ regeneration in KRas-mutant lung adenocarcinoma. https://doi.org/10.1101/2022.06.01.494337

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