Lack of Cytochrome c in Mouse Fibroblasts Disrupts Assembly/Stability of Respiratory Complexes I and IV

Department of Neurology and Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2009; 284(7):4383-91. DOI: 10.1074/jbc.M805972200
Source: PubMed


Cytochrome c (cyt c) is a heme-containing protein that participates in electron transport in the respiratory chain and as a signaling molecule in the apoptotic cascade. Here we addressed the effect of removing mammalian cyt c on the integrity of the respiratory complexes in mammalian cells. Mitochondria from cyt c knockout mouse cells lacked fully assembled complexes I and IV and had reduced levels of complex III. A redox-deficient mutant of cyt c was unable to rescue the levels of complexes I and IV. We found that cyt c is associated with both complex IV and respiratory supercomplexes, providing a potential mechanism for the requirement for cyt c in the assembly/stability of complex IV.

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    • "This result seems inconsistency, but mitochondrial membrane permeabilization is a complex process and includes several mechanisms such as Bcl-2 family proteins regulation and lipid peroxidation, therefore the simplest explanation is that other reasons that affect Δψ might to be remained which needed further research. In recent years, works from several laboratories showed that the mitochondrial membrane potential was essential for the membrane anchorage of the respiratory supercomplexes [40], which might serve to reduce the diffusion distance of the substrates, to improve electron transfer, to decrease the reactive oxygen species formation and to stabilize the individual complexes [41]. In our study, we found that the stability of mitochondrial membrane potential promoted PMA-induced cell differentiation, possibly because of the increased stability of supercomplexes. "
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    • "revealed that: (iii) isolated respirasomes mediate electron transfer from NADH to O 2 and (iv) respirasomes can contain CoQ 10 and cyt-c. The latter suggests that also cyt-c is associated with respiratory supercomplexes, compatible with the observation that fibroblasts from cyt-c knockout mice lacked fully assembled CI and CIV and displayed lower levels of CIII (Vempati et al, 2009), and evidence that cyt-c and CoQ 10 are functionally compartmentalized (Benard et al, 2008). The first protein factor (HIGD2A) required for respirasome assembly and stability in mammals was recently identified (Chen et al, 2012; Strogolova et al, 2012; Vukotic et al, 2012). "
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    • "In addition to its role as electron carrier in the mitochondrial respiratory chain, CYTc has been linked to other important cellular processes , triggering programmed cell death in mammals [16] and participating in the redox-mediated import of proteins to the intermembrane space in yeast [17]. Mutant analyses in yeast and mammals revealed that CYTc is structurally required for the assembly and stability of Complexes I, III and IV [18] [19] [20]. A binding site for CYTc within the structure of respiratory supercomplexes was proposed in yeast [21] suggesting that this supramolecular configuration could be the basis for efficient electron transfer from Complex III to Complex IV [22]. "
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