TY - JOUR
T1 - MDM2 Integrates Cellular Respiration and Apoptotic Signaling through NDUFS1 and the Mitochondrial Network
AU - Elkholi, Rana
AU - Abraham-Enachescu, Ioana
AU - Trotta, Andrew P.
AU - Rubio-Patiño, Camila
AU - Mohammed, Jarvier N.
AU - Luna-Vargas, Mark P.A.
AU - Gelles, Jesse D.
AU - Kaminetsky, Joshua R.
AU - Serasinghe, Madhavika N.
AU - Zou, Cindy
AU - Ali, Sumaira
AU - McStay, Gavin P.
AU - Pfleger, Cathie M.
AU - Chipuk, Jerry Edward
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/5/2
Y1 - 2019/5/2
N2 - 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.
AB - 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.
KW - BCL-2 family
KW - MDM2
KW - NDUFS1
KW - apoptosis
KW - complex I
KW - mitochondria
UR - https://www.scopus.com/pages/publications/85064871496
U2 - 10.1016/j.molcel.2019.02.012
DO - 10.1016/j.molcel.2019.02.012
M3 - Article
C2 - 30879903
AN - SCOPUS:85064871496
SN - 1097-2765
VL - 74
SP - 452-465.e7
JO - Molecular Cell
JF - Molecular Cell
IS - 3
ER -