Cytochrome C oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane. The complex consists of 13 mitochondrial- and nuclear-encoded subunits. The mitochondrially-encoded subunits perform the electron transfer and proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex. This gene encodes the nuclear-encoded subunit Vb of the human mitochondrial respiratory chain enzyme.
Cytochrome c oxidase IV (COX4) is component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. COX4 is a nuclear-encoded subunit of COX that may play a role in regulating COX activity. COX4 is expressed ubiquitously in adult human tissue with the strongest levels of expression in the pancreas and moderate expression levels in heart, skeletal muscle and placenta.
Co-chaperonin implicated in mitochondrial protein import and macromolecular assembly. Together with Hsp60, facilitates the correct folding of imported proteins. May also prevent misfolding and promote the refolding and proper assembly of unfolded polypeptides generated under stress conditions in the mitochondrial matrix. The functional units of these chaperonins consist of heptameric rings of the large subunit Hsp60, which function as a back-to-back double ring. In a cyclic reaction, Hsp60 ring complexes bind one unfolded substrate protein per ring, followed by the binding of ATP and association with 2 heptameric rings of the co-chaperonin Hsp10. This leads to sequestration of the substrate protein in the inner cavity of Hsp60 where, for a certain period of time, it can fold undisturbed by other cell components. Synchronous hydrolysis of ATP in all Hsp60 subunits results in the dissociation of the chaperonin rings and the release of ADP and the folded substrate protein.
Carbamoyl phosphate synthetase 1 (CPS1), a rate-limiting enzyme in the urea cycle, catalyzes the conversion of ammonia and bicarbonate to carbamoyl phosphate in mitochondria. Non-small cell lung carcinoma (NSCLC) cells with oncogenic KRAS and loss of the tumor suppressor LKB1 express CPS1 and depend on this enzyme for growth. CPS1 maintains pyrimidine/purine balance in these cancer cells. Silencing CPS1 reduces the pyrimidine to purine ratio and stalls DNA synthesis, leading to DNA damage and cancer cell death. In addition, the tumor suppressor p53 represses the expression of urea cycle enzymes CPS1, OTC, and ARG1 and, therefore, causes the accumulation of ammonia, suppressing cancer growth. Furthermore, research studies suggest that hypermethylation-mediated downregulation of CPS1 expression may contribute to the progression of normal hepatocytes to hepatocellular carcinoma (HCC).
The mitochondrial oxidation of long-chain fatty acids is initiated by the sequential action of carnitine palmitoyltransferase I (which is located in the outer membrane and is detergent-labile) and carnitine palmitoyltransferase II (which is located in the inner membrane and is detergent-stable), together with a carnitine-acylcarnitine translocase. CPT I is the key enzyme in the carnitine-dependent transport across the mitochondrial inner membrane and its deficiency results in a decreased rate of fatty acid beta-oxidation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.
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