ATP synthase F0 complex subunit C3 (ATP5MC3)

ATP synthase F0 complex subunit C3, encoded by the ATP5MC3 gene, is a critical component of the mitochondrial F1F0 ATP synthase (Complex V). It forms part of the transmembrane c-ring within the F0 domain, which functions as a rotary proton channel driven by the electrochemical gradient across the inner mitochondrial membrane (UniProt P48201). The rotation of this c-ring is mechanically coupled to the F1 catalytic domain, enabling the synthesis of ATP from ADP and inorganic phosphate (PubMed: 29162618). In humans, this subunit is one of three isoforms (along with C1 and C2) that are identical or nearly identical in protein sequence and contribute to the same functional enzyme complex (HGNC: 843). Pathologically, the failure to properly degrade this proteolipid leads to its accumulation in lysosomes, a hallmark of Neuronal Ceroid Lipofuscinosis or Batten disease (PubMed: 1554493). While it is a target for potent inhibitors like oligomycin, which are used extensively in metabolic research, its essential role in life makes it a challenging target for systemic human therapeutics due to the risk of global metabolic failure. However, it remains a subject of intense study in the context of mitochondrial diseases, cancer metabolism, and the regulation of the mitochondrial permeability transition pore.

Other names

ATP5G3ATP synthase lipid-binding protein, mitochondrialATP synthase proteolipid P3ATP synthase subunit c isoform 3ATPase protein 9 isoform 3ATP synthase membrane subunit c locus 3

Inhibition of the F0 proton channel by binding to the c-ring subunits, which physically blocks proton translocation across the inner mitochondrial membrane and halts the rotation of the ATP synthase enzyme, thereby preventing the phosphorylation of ADP to ATP.