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

Elkholi, Rana, Abraham-Enachescu, Ioana, Trotta, Andrew P., Rubio-Patiño, Camila, Mohammed, Jarvier N., Luna-Vargas, Mark P.A., Gelles, Jesse D., Kaminetsky, Joshua R., Serasinghe, Madhavika N., Zou, Cindy, Ali, Sumaira, MCSTAY, Gavin, Pfleger, Cathie M. and Chipuk, Jerry Edward (2019) MDM2 Integrates Cellular Respiration and Apoptotic Signaling through NDUFS1 and the Mitochondrial Network. Molecular Cell. ISSN 10972765 (In Press)

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Abstract or description

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.

Item Type: Article
Faculty: School of Life Sciences and Education > Biological Sciences
Depositing User: Gavin MCSTAY
Date Deposited: 11 Apr 2019 15:02
Last Modified: 11 Apr 2019 15:02
URI: http://eprints.staffs.ac.uk/id/eprint/5461

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