Cytochrome c

Abstract

What is it? Cytochrome c is an essential component of the mitochondrial respiratory chain… but this much is textbook stuff. Cytochrome c has become trendy again recently, not as part of the powerhouse of the cell, but because of its involvement in programmed cell death (apoptosis). Not to be confused with… cytochrome a, cytochrome b–c1 (both enzyme complexes in the same mitochondrial respiratory chain), or phytochromes (nothing to do with mitochondria; they're plant light-absorption proteins). How is it made? Cytochrome c is synthesized from two inactive precursor molecules: apocytochrome c (a protein that is encoded by a nuclear gene and imported into mitochondria) and heme (which is synthesized in mitochondria). The covalent attachment of apocytochrome c to heme is catalyzed by heme lyase and creates cytochrome c, a 14.5 kDa protein that is normally confined to the intermembrane space (between the inner and outer mitochondrial membranes). How does it work? Because of its heme group, cytochrome c can shuttle electrons, which it does between respiratory chain complexes III (cytochrome reductase) and IV (cytochrome c oxidase) (see Figure 1). Without cytochrome c, electron flow would be interrupted, with two potentially lethal consequences: loss of ATP synthesis and overproduction of the radical superoxide anion because of incomplete oxidation. So, how is it lethal? It's not only the loss of respiratory activity that seems to be important in apoptosis, it's the release of cytochrome c from mitochondria that causes problems. During apoptosis, cytochrome c is released through the outer mitochondrial membrane (see Figure 1). This allows it to interact with Apaf-1 (apoptosis protease activating factor-1), which activates pro-caspase-9. Caspase-9 then triggers other caspases. In other words, ectopic cytochrome c unleashes the killer caspases, which leads to proteolytic destruction of the cell. How is cytochrome c released? Well, it just seems to happen. In mammalian cells undergoing apoptosis, all soluble intermembrane proteins (SIMPs) are released through the outer membrane of mitochondria and, so far, no specific mechanism for cytochrome c release has been found. It has been proposed that swelling of the mitochondrial matrix during apoptosis causes local disruption of the outer mitochondrial membrane, which has a smaller surface than the convoluted inner membrane that surrounds the matrix. Alternatively, proteins in the outer membrane might oligomerize to form a giant permeability transition pore (PTP) complex (which might involve pro-apoptotic proteins such as Bax). Is it there any way of preventing release? Release of SIMPs, including cytochrome c, can be prevented by proteins of the Bcl-2 family. Such proteins neutralize Bax and/or act on the permeability transition pore, a complex that controls mitochondrial membrane permeability. Is it the only mitochondrial apoptogenic factor? No, although many assumed it would be. Mitochondria release other apoptogenic proteins including pro-caspases, hsp60 (which is involved in pro-caspase activation) and apoptosis-inducing factor (AIF). So, is it really important in apoptosis? A lot of people thought that caspase activation by cytochrome c would be absolutely essential for cell death. But it's now known that even without caspases the cells still die, they just don't exhibit the normal signs of apoptosis. It's also turned out that Bcl-2 must do more than just retain cytochrome c — and all other SIMPs — within the mitochondrion to prevent apoptosis. In particular, it must maintain the function of the inner membrane. So, instead of being a major protagonist in the apoptotic response, cytochrome c seems to be simply one SIMP among many. Life and death decisions are made not by cytochrome c itself but rather by whatever causes its release from the mitochondria. G Kroemer, CNRS-ERS1984, 19 rue Guy Môquet, F-94801 Villejuif, France.