NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (NDUFS7) (NDUFS7)

NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (NDUFS7), also known as the PSST subunit, is a core nuclear-encoded subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) [10, 18]. It is a key component of the "Q-module" located at the interface of the enzyme's peripheral and membrane arms, where it forms the ubiquinone-binding pocket alongside the NDUFS2 subunit [1, 13]. NDUFS7 contains a highly conserved 4Fe-4S cluster, designated N2, which serves as the immediate electron donor to ubiquinone, making it essential for the first step of the electron transport chain and ATP synthesis [12, 18]. Mutations in the NDUFS7 gene are a well-established cause of Leigh syndrome and other forms of mitochondrial complex I deficiency, characterized by severe neurological impairment and metabolic acidosis [7, 20, 23]. Beyond its role in bioenergetics, NDUFS7 is a critical mediator of cellular oxygen sensing, particularly in the carotid body and pulmonary vasculature, where it facilitates the hypoxic pulmonary vasoconstriction response [2, 4, 9]. In oncology, NDUFS7 has emerged as a therapeutic target for cancers with high oxidative phosphorylation dependency, such as pancreatic cancer and acute myeloid leukemia [6, 13, 15]. Drugs targeting this subunit, including classic inhibitors like rotenone and novel antagonists like DX2-201, act by blocking the ubiquinone-binding site, thereby disrupting mitochondrial function and inducing apoptosis in susceptible cells [13, 14].

Other names

PSST subunitCI-20kDNADH-ubiquinone oxidoreductase 20 kDa subunitComplex I-20kDMY017NADH:ubiquinone oxidoreductase core subunit S7

Inhibition of the ubiquinone-binding site of mitochondrial complex I, preventing electron transfer from iron-sulfur cluster N2 to ubiquinone and disrupting the proton gradient [12, 13, 14].