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

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. [Display omitted] •Independent of its canonical activities, MDM2 can promote cell death•Cytosolic MDM2 causes oxidative stress, DNA damage, and apoptosis•Cytosolic MDM2 sequesters NDUFS1 to destabilize CI·CIII assembly and enhance ROS•Mitigation of MDM2-induced mitochondrial ROS prevents DNA damage and subsequent apoptosis Elkholi et al. show that the cytosolic accumulation of MDM2 leads to the sequestration of NDUFS1, a critical Fe/S cluster in complex I that promotes efficient mitochondrial respiration. Following MDM2 association with NDUFS1, ROS production increases, which can cause DNA damage and subsequent activation of the mitochondrial pathway of apoptosis.