EndoG Links Bnip3-Induced Mitochondrial Damage and Caspase-Independent DNA Fragmentation in Ischemic Cardiomyocytes

Abstract

Mitochondrial dysfunction, caspase activation and caspase-dependent DNA fragmentation are involved in cell damage in many tissues. However, differentiated cardiomyocytes repress the expression of the canonical apoptotic pathway and their death during ischemia is caspase-independent. The atypical BH3-only protein Bnip3 is involved in the process leading to caspase-independent DNA fragmentation in cardiomyocytes. However, the pathway by which DNA degradation ensues following Bnip3 activation is not resolved. To identify the mechanism involved, we analyzed the interdependence of Bnip3, Nix and EndoG in mitochondrial damage and DNA fragmentation during experimental ischemia in neonatal rat ventricular cardiomyocytes. Our results show that the expression of EndoG and Bnip3 increases in the heart throughout development, while the caspase-dependent machinery is silenced. TUNEL-positive DNA damage, which depends on caspase activity in other cells, is caspase-independent in ischemic cardiomyocytes and ischemia-induced DNA high and low molecular weight fragmentation is blocked by repressing EndoG expression. Ischemia-induced EndoG translocation and DNA degradation are prevented by silencing the expression of Bnip3, but not Nix, or by overexpressing Bcl-xL. These data establish a link between Bnip3 and EndoG-dependent, TUNEL-positive, DNA fragmentation in ischemic cardiomyocytes in the absence of caspases, defining an alternative cell death pathway in postmitotic cells.

Caspase-Dependent and Caspase-Independent Pathways Are Involved in Cadmium-Induced Apoptosis in Primary Rat Proximal Tubular Cell Culture

“…BNIP-3 and AIF cooperate to induce apoptosis and cavitation in epithelial morphogenesis [16]. Meanwhile, silencing BNIP-3 prevents Endo G translocation and DNA degradation [49]. We found that BNIP-3 protein levels and AIF and Endo G translocation were increased during cadmium-induced rPT cell apoptosis, while BNIP-3 silencing decreased AIF and Endo G translocation.…”

DNase activation by hypoxia–acidosis parallels but is independent of programmed cell death

“…There have been several reports that AIF and EndoG translocate to the nuclei during neuronal and myocardial ischemia coincident with Bnip3 activation (Hamacher-Brady et al, 2006; Zhang et al, 2011; Zhang et al, 2007). In one of these, Zhang et al, (2011) reported caspase-independent, Bnip3-dependent release of EndoG in cardiac myocytes subjected to simulated ischemia.…”

“…In one of these, Zhang et al, (2011) reported caspase-independent, Bnip3-dependent release of EndoG in cardiac myocytes subjected to simulated ischemia. Our studies suggest that AIF translocation accompanies Bnip3-mediated cell death during hypoxia/acidosis but this translocation is not dependent on Bnip3, mPTP, or calpains.…”

Different molecular mechanisms involved in spontaneous and oxidative stress-induced mitochondrial fragmentation in tripeptidyl peptidase-1 (TPP-1)-deficient fibroblasts

“…These authors also mentioned that this resistance is no longer observed when cells are treated with ceramide or staurosporine, two apoptosis inducers acting through mitochondrial dysfunction, suggesting that this pathway could be involved in the induced neurodegeneration of cells affected by a TPP-1 deficiency [6]. The fact that BNIP3-mediated cell death was shown to be independent of caspase 3 and cytochrome c release in some cell types [24,62], argues in favour of a putative role of BNIP3 in the cell death observed in LINCL cells exposed to an external stress. As proposed by Zhao and co-workers, the BNIP3-mediated cell death would mainly involve the nuclear translocation of endonuclease G, an apoptotic DNase when released from mitochondria [63].…”