Mitochondrial ATP synthase and NADH dehydrogenase (Complex V and Complex I)

Mitochondrial ATP synthase (Complex V) and NADH dehydrogenase (Complex I) are essential multi-subunit enzymes within the mitochondrial oxidative phosphorylation (OXPHOS) system (UniProt, 2024). NADH dehydrogenase initiates the electron transport chain by transferring electrons from NADH to ubiquinone, a process coupled with proton pumping across the inner membrane (PubMed: 11017181). ATP synthase subsequently utilizes the established proton motive force to drive the phosphorylation of ADP into ATP, the cell's primary energy currency (PubMed: 14614053). These complexes play a central role in cellular metabolism, and their dysfunction is a hallmark of many genetic mitochondrial diseases, such as Leber hereditary optic neuropathy (LHON) and Leigh syndrome (NIH, 2023). In the context of cancer, these enzymes are increasingly viewed as therapeutic targets because many tumors depend on OXPHOS for growth and survival under stress (PubMed: 30842677). Pharmacological inhibition of Complex I by drugs like metformin has shown efficacy in managing type 2 diabetes and is being explored for anti-cancer properties (PubMed: 10839993). Conversely, inhibitors of ATP synthase, such as oligomycin or novel small molecules like Gboxin, are used as tools to study metabolic flux and are being investigated for potential therapeutic applications in hyperproliferative diseases (PubMed: 30842677). Targeting these complexes requires careful management due to the risk of systemic toxicity and lactic acidosis, given their fundamental role in global energy homeostasis (PubMed: 25134311).

Other names

Complex I and Complex VNADH:ubiquinone oxidoreductase and F1Fo-ATP synthaseOXPHOS Complex I and VMitochondrial respiratory chain complexes I and V

Inhibition of NADH oxidation at Complex I and/or inhibition of the proton-driven ATP synthesis at Complex V to disrupt mitochondrial bioenergetics and reduce cellular ATP levels (PubMed: 10839993, PubMed: 30842677).