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Updated: Aug 17, 2025

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

Dane T Sessions1, Kee-Beom Kim1, Jennifer A Kashatus1

  • 1Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA.

Cell Reports
|December 14, 2022
PubMed

Insights

Oncogenic KRas lung cancer growth depends on Opa1, not Drp1. Opa1 loss disrupts mitochondrial structure and function, inhibiting tumor growth by reducing NAD+ regeneration.

Area of Science:

  • Mitochondrial biology
  • Cancer research
  • Molecular oncology

Background:

  • Oncogenic KRas drives tumorigenesis, often involving mitochondrial dynamics.
  • The role of mitochondrial fission (Drp1) and fusion (Opa1) in KRas-driven lung cancer is unclear.

Purpose of the Study:

  • To investigate the roles of Drp1 and Opa1 in KRas-driven lung adenocarcinoma growth.
  • To elucidate the underlying mechanisms of mitochondrial dynamics in this cancer model.

Main Methods:

  • Utilized knockout models for Drp1 and Opa1 in KRas-driven lung adenocarcinoma cells.
  • Assessed tumor cell proliferation, mitochondrial morphology, electron transport chain (ETC) activity, and NAD+ regeneration.
  • Employed both in vitro and in vivo experimental systems.

Main Results:

  • Drp1 deletion did not affect KRas-driven lung adenocarcinoma growth.
  • Opa1 deletion significantly inhibited tumor growth by disrupting mitochondrial cristae morphology and ETC function.
  • Opa1 loss led to reduced NAD+ regeneration, impairing tumor cell proliferation.
  • Simultaneous deletion of Drp1 and Opa1 restored mitochondrial structure, ETC activity, and proliferation, suggesting fission exacerbates Opa1 loss-induced dysfunction.

Conclusions:

  • Opa1, crucial for mitochondrial inner membrane fusion and cristae integrity, is essential for KRas-driven lung adenocarcinoma.
  • Mitochondrial fission, when hyperactive, can disrupt ETC function, making Opa1 critical for maintaining tumor cell viability.
Keywords:
CP: CancerDrp1ETCKRasNADOpa1cancercristaefissionfusionmitochondria

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