Caspase cleavage of cytochrome c1 disrupts mitochondrial function and enhances cytochrome c release

Abstract

Mitochondrial catastrophe can be the cause or consequence of apoptosis and is associated with a number of pathophysiological conditions. The exact relationship between mitochondrial catastrophe and caspase activation is not completely understood. Here we addressed the underlying mechanism, explaining how activated caspase could feedback to attack mitochondria to amplify further cytochrome c (cyto.c) release. We discovered that cytochrome c1 (cyto.c1) in the bc1 complex of the mitochondrial respiration chain was a novel substrate of caspase 3 (casp.3). We found that cyto.c1 was cleaved at the site of D106, which is critical for binding with cyto.c, following apoptotic stresses or targeted expression of casp.3 into the mitochondrial intermembrane space. We demonstrated that this cleavage was closely linked with further cyto.c release and mitochondrial catastrophe. These mitochondrial events could be effectively blocked by expressing non-cleavable cyto.c1 (D106A) or by caspase inhibitor z-VAD-fmk. Our results demonstrate that the cleavage of cyto.c1 represents a critical step for the feedback amplification of cyto.c release by caspases and subsequent mitochondrial catastrophe.

Respiratory complexes III and IV can each bind two molecules of cytochrome c at low ionic strength

“…The organization of the mitochondrial electron transport chain is a subject of intense debate at present, where two different models are being considered: the fluid model, that proposes a random organization for individual respiratory protein components, and the solid model, suggesting a stable association between individual complexes [6][7][8]. Apart their role in respiration, Cc and Cc 1 are clearly involved in the development of programmed cell death [9][10][11][12][13][14][15]. Such a dual role of Cc is regulated by post-translational modifications -namely, phosphorylation and nitration of tyrosine residues -that affect the binding of Cc to its physiological counterparts, either in the mitochondria or in the cytoplasm [16][17][18][19][20][21][22][23].…”

CYC1 Silencing Sensitizes Osteosarcoma Cells to TRAIL-Induced Apoptosis

“…4A and 4B). It has been reported that caspase-3 amplifies Cytc release and mitochondria fragmentation by cleaving CYC1 during mitochondria-dependent apoptosis [11]. In the mitochondrial electron transport chain, CYC1 directly interacts and stabilizes Cytc.…”

“…Interestingly, a recent study reported that CYC1 cleavage by caspase-3 disrupts mitochondrial function and enhances Cyt c release and apoptosis [11]. Thus, we speculated that CYC1 downregulation in OS might sensitize OS cells to apoptotic induction by TRAIL through promoting Cyt c release.…”

Repurposing L-Menthol for Systems Medicine and Cancer Therapeutics? L-Menthol Induces Apoptosis through Caspase 10 and by Suppressing HSP90

“…The other pro-apoptotic or antiproliferative protein genes downregulated were DAPK3 (Kawai et al, 1998), BMF (Puthalakath et al, 2001), RBL2 (Dick, 2007), RBBP2 (Chicas et al, 2012), BNIP3 (Burton et al, 2013), APP (Takahashi et al, 2009) Table S2). Similarly, anti-apoptotic/cell proliferation genes downregulated are CACNB4 (Tadmouri et al, 2012), TNFRSF11B (Oliver et al, 2013), CAPN6 (Rho et al, 2008), GRB2 (Kraskouskaya et al, 2013), TRAF6 (Wong et al, 1999), BZRP (Maaser et al, 2002), TNFRSF6B (Chen et al, 2010), RAF1 (McPhillips et al, 2006), CYC1 (Zhu et al, 2012), and HSPD1 (Ghosh et al, 2008) (Supplementary Table S2). …”