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

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 show that in vitro and in vivo growth of KRas-driven lung adenocarcinoma is unaffected by deletion of Drp1 but is inhibited by deletion of Opa1, the GTPase that regulates inner membrane fusion and proper cristae morphology. Mechanistically, Opa1 knockout disrupts cristae morphology and inhibits electron transport chain (ETC) assembly and activity, which inhibits tumor cell proliferation through loss of NAD⁺ regeneration. Simultaneous inactivation of Drp1 and Opa1 restores cristae morpholo

SUBMITTER: Sessions DT 

PROVIDER: S-EPMC10265649 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature