Mitochondrial Pruning by Nix and BNip3: An Essential Function for Cardiac-Expressed Death Factors

Abstract

Programmed cardiac myocyte death via the intrinsic, or mitochondrial, pathway is a mechanism of pathological ventricular remodeling after myocardial infarction and during chronic pressure overload hypertrophy. Transcriptional upregulation of the closely related proapoptotic Bcl2 family members BNip3 in ischemic myocardium and Nix in hypertrophied myocardium suggested a molecular mechanism by which programmed cell death can be initiated by cardiac stress and lead to dilated cardiomyopathy. Studies using transgenic and gene knockout mice subsequently demonstrated that expression of BNip3 and Nix is both sufficient for cardiomyopathy development and necessary for cardiac remodeling after reversible coronary occlusion and transverse aortic banding, respectively. Here, these data are reviewed in the context of recent findings showing that Nix not only stimulates cardiomyocyte apoptosis but also induces mitochondrial autophagy (mitophagy) and indirectly activates the mitochondrial permeability transition pore, causing cell necrosis. New findings are presented suggesting that Nix and BNip3 have an essential function, "mitochondrial pruning," that restrains mitochondrial proliferation in cardiomyocytes and without which an age-dependent mitochondrial cardiomyopathy develops. KeywordsApoptosis; Heart Failure; Mitochondria; Autophagy BNip3 and Nix are Inducible Cardiomyocyte Death FactorsThe cellular hallmark of acquired dilated cardiomyopathy is loss of functioning cardiomyocytes, frequently with their replacement by fibrotic tissue [1]. In the case of myocardial infarction, this "cardiomyocyte drop-out" is early and localized and constitutes the primary injury. In chronically ischemic hearts and nonischemic cardiomyopathies, cardiomyocyte drop-out (typically characterized in the literature as apoptosis) is widespread and induced as a programmed secondary response to the primary injury [2][3][4][5]. Because adult cardiac myocytes are incapable of meaningful cellular regeneration [6], chronic persistent apoptosis at a rate of 0.1-1% of total cardiomyocytes is sufficient to produce cardiac dilation and heart failure [7]. The workload placed on the heart by programmed cardiac myocyte loss initiates a feed-forward cycle of unfavorable geometrical remodeling that further induces cardiomyocyte death genes, resulting in a downward functional spiral progressing to dilated cardiomyopathy and end-stage heart failure [8,9].Cardiomyocyte apoptosis can be mediated either through the extrinsic cytokine death receptor pathway, or the intrinsic mitochondrial pathway. The focus here is on mitochondrial apoptosis, regulated by the Bcl2 family of mitochondrial-targeted pro-and anti-"apoptotic" proteins. These factors unambiguously regulate caspase-dependent apoptosis and so the moniker of "pro-" or "anti-apoptotic" is at least partially correct. As explained in more detail below, however, evidence is accumulating that Bcl2 family proteins also regulate nonapoptotic forms of programmed cell death that occur concomitantly and can be ...

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“…This complex dual role is also evident in studies with BNIP3-deficient mice. These mice are more resistant to myocardial I/R (Diwan et al 2007) but accumulate dysfunctional mitochondria in myocytes with aging (Dorn 2010).…”

HDAC8-Mediated Epigenetic Reprogramming Plays a Key Role in Resistance to Anthrax Lethal Toxin–Induced Pyroptosis in Macrophages

“…Therefore, it will be interesting to examine whether edema toxin potentiates LeTx-induced cytotoxic and pathophysiologic effects (51, 52) through inhibiting HDAC8 and inducing the mitochondrial death genes. Enhanced expression of the mitochondrial death genes BNIP3, BNIP3L, and MLN64 can cause cytotoxicity and is involved in hypoxia-induced cardiovascular pathology (53)(54)(55)(56), which is also observed in anthrax animal models (57,58).…”

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