MDM2 Integrates Cellular Respiration and Apoptotic Signaling through NDUFS1 and the Mitochondrial Network

Rana Elkholi, Ioana Abraham-Enachescu, Andrew P. Trotta, Camila Rubio-Patiño, Jarvier N. Mohammed, Mark P.A. Luna-Vargas, Jesse D. Gelles, Joshua R. Kaminetsky, Madhavika N. Serasinghe, Cindy Zou, Sumaira Ali, Gavin P. McStay, Cathie M. Pfleger, Jerry Edward Chipuk

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Signaling diversity and subsequent complexity in higher eukaryotes is partially explained by one gene encoding a polypeptide with multiple biochemical functions in different cellular contexts. For example, mouse double minute 2 (MDM2)is functionally characterized as both an oncogene and a tumor suppressor, yet this dual classification confounds the cell biology and clinical literatures. Identified via complementary biochemical, organellar, and cellular approaches, we report that MDM2 negatively regulates NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1), leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis. MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial localization and ultimately causing complex I and supercomplex destabilization and inefficiency of oxidative phosphorylation. The MDM2 amino-terminal region is sufficient to bind NDUFS1, alter supercomplex assembly, and induce apoptosis. Finally, this pathway is independent of p53, and several mitochondrial phenotypes are observed in Drosophila and murine models expressing transgenic Mdm2.

Original languageEnglish
Pages (from-to)452-465.e7
JournalMolecular Cell
Volume74
Issue number3
DOIs
StatePublished - 2 May 2019

Keywords

  • BCL-2 family
  • MDM2
  • NDUFS1
  • apoptosis
  • complex I
  • mitochondria

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