Cycs

Cycs Background

Cytochrome c (Cytc) is a water-soluble protein in humans that is encoded by the CYCS gene. Cytochrome c is initially synthesized as an apocytochrome c lacking heme in the cytoplasm. The heme prosthetic group is covalently ligated to the apocytochrome c peptide chain via two (or very rarely one) thioether linkages between the vinyl groups of heme and two cysteines sulfhydryls of a conserved CysXxxXxxCysHis (CXXCH) heme-binding motif ^[1][2]. The reaction is catalyzed by cytochrome c heme lyase (CCHL) ^[3]. The addition of heme to an apocytochrome c is a requirement for cytochrome c import into mitochondria ^[3][4]. Mature cytochrome c is located in the mitochondrial intermembrane space (IMS) and loosely attached to the surface of the inner mitochondrial membrane ^[5]. Cytochrome c is functionally involved in the electron transport chain (ETC) of mitochondria. Electron transport is part of the pathway for the synthesis of ATP. The oxidized form of the cytochrome c heme group can accept an electron from the heme group of the cytochrome c1 subunit of cytochrome reductase. Cytochrome c and then transfers this electron to the cytochrome oxidase complex, and the final protein carrier in the mitochondrial electron-transport chain ^[6]. Cytc is essential for aerobic energy production, and cytochrome c-null mice died around midgestation ^[8]. In addition to its role in mitochondrial respiration, cytochrome c plays a crucial role in apoptotic signaling ^[7]. Cytochrome c is a pivotal protein that initiates the intrinsic apoptosis pathway. Stimulated by apoptotic signals, mitochondrial outer membrane permeability (MOMP) is enhanced, leading to the release of cytochrome c into the cytosol. Free cytochrome c binds to apoptotic protease-activating factor 1 (Apaf-1), forming an apoptosome that then switches on caspases. These enzymes chew up cellular proteins, inducing apoptosis. The release of cytochrome c and cytochrome-c-mediated apoptosis are prominently controlled and regulated by the members of the B-cell lymphoma protein-2 (BCL2) family ^[9]. Interestingly, cytochrome c itself undergoes antiapoptotic modification by glucose metabolism. Allyson E. Vaughn and Mohanish Deshmuk showed that NADPH derived from the pentose phosphate pathway controls redox state of cytochrome c and indicated that glucose metabolism negatively regulates apoptosis even downstream of MOMP through the production of NADPH ^[10]. Recent discoveries of additional functions of cytochrome c, including its activity as a cardiolipin peroxidase ^[11][12] and the detection of four phosphorylation sites on cytochrome c ^[13], suggest that its multiple functions are regulated by cell signaling pathways.

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[9] Yong-Ling P. Ow, Douglas R. Green, et al. Cytochrome c: functions beyond respiration [J]. Nature Reviews Molecular Cell Biology volume 9, 2008, pages532–542.
[10] Allyson E. Vaughn & Mohanish Deshmuk. Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c [J]. Nature Cell Biology volume 10, 2008, pages1477–1483.
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[12] Kagan VE, Tyurin VA, et al. Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors [J]. Nat Chem Biol. 2005 Sep; 1(4):223-32.
[13] Zhao X, León IR, et al. Phosphoproteome analysis of functional mitochondria isolated from resting human muscle reveals extensive phosphorylation of inner membrane protein complexes and enzymes [J]. Mol Cell Proteomics. 2011 Jan; 10(1):M110.000299.