NDUFS1 is a nuclear encoded structural subunit of NADH: ubiquinone oxidoreductase (complex 1) in the mitochondrial electron transport chain. Mutations in NDUFS1 and other complex 1 subunits leading to mitochondrial dysfunction are associated with a number of neurological disorders. High-fat diet associated with type 2 diabetes leads to decreased expression of complex 1 subunits, including NDUFS1. NDUFS1 is the target of cleavage by apoptotic caspases contributing to the loss of mitochondrial transmembrane potential, compromised mitochondrial respiration, increased mitochondrial reactive oxygen species production, and loss of lysosomal integrity. NDUFS1 can also be cleaved by the lymphocyte protease granzyme B. Studies have also found that MDM2, which has a canonical role as an inhibitor of the tumor suppressor p53, can also sequester NDUFS1 in the cytoplasm, leading to respiratory dysfunction and increases in ROS.
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