Mitochondrial shaping proteins as novel treatment targets for cardiomyopathies

Abstract

Heart failure (HF) is one of the leading causes of death and disability worldwide. The prevalence of HF continues to rise, and its outcomes are worsened by risk factors such as age, diabetes, obesity, hypertension, and ischemic heart disease. Hence, there is an unmet need to identify novel treatment targets that can prevent the development and progression of HF in order to improve patient outcomes. In this regard, cardiac mitochondria play an essential role in generating the ATP required to maintain normal cardiac contractile function. Mitochondrial dysfunction is known to contribute to the pathogenesis of a number of cardiomyopathies including those secondary to diabetes, pressure-overload left ventricular hypertrophy (LVH), and doxorubicin cardiotoxicity. Mitochondria continually change their shape by undergoing fusion and fission, and an imbalance in mitochondrial fusion and fission have been shown to impact on mitochondrial function, and contribute to the pathogenesis of these cardiomyopathies. In this review article, we focus on the role of mitochondrial shaping proteins as contributors to the development of three cardiomyopathies, and highlight their therapeutic potential as novel treatment targets for preventing the onset and progression of HF.

Keywords: Mitochondrial morphology; diabetic cardiomyopathy; doxorubicin cardiotoxicity; heart failure; left ventricular hypertrophy.

Figure 1.

Targeting mitochondrial shaping proteins as treatment strategy for diabetic cardiomyopathy. High-glucose and lipotoxicity (from free fatty acids including palmitate) induce activation and mitochondrial translocation of Drp1, suppression of Mfn2 and OPA1, mitochondrial fission, increased ROS production, MPTP opening, and cell death through different signalling pathways. These pathways can be targeted by therapies such as melatonin, eicosapentanenoic acid, Trimetazidine, mdivi-1, and exercise to prevent onset and progression of diabetic cardiomyopathy. Dynamin-related protein 1, Drp1; optic atrophy protein 1, OPA1; mitofusin 2, Mfn2; mitochondrial permeability transition pore, MPTP; trimetazidine, TMZ; O-linked N-acetyl-glucosamine glycosylation, O-GlcNAcylation; reactive oxygen species, ROS; 5’ AMP-activated protein kinase, AMPK; peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC1α; voltage dependant anion channels, VDAC; extracellular regulated kinase, Erk.

Figure 2.

Targeting mitochondrial shaping proteins as a treatment strategy for pressure-overload left ventricular hypertrophy (LVH) and cardiomyopathy. Pressure-overload LVH by total aortic constriction induce activation and mitochondrial translocation of Drp1, mitochondrial fission, increased ROS production, and MPTP opening through different signalling pathways. These pathways can be targeted by therapies such as mdivi-1 to prevent onset and progression of LVH and cardiomyopathy. Dynamin-related protein 1, Drp1; fission protein 1, Fis1; mitochondrial permeability transition pore, MPTP; reactive oxygen species, ROS; angiotensin II, Ang II.

Figure 3.

Targeting mitochondrial shaping proteins as treatment strategy for doxorubicin cardiotoxicity. Doxorubicin induces activation and mitochondrial translocation of Drp1, reduction of Mfn2, mitochondrial fission, increased ROS production, MPTP opening, pyroptosis, and cell death through different signalling pathways. These pathways can be targeted by therapies such as liensinine, LCZ696, exercise, cyclosporine-A, mdivi-1, Mito-TEMPO to protect against doxorubicin cardiotoxicity. Dynamin-related protein 1, Drp1; optic atrophy protein 1, Mfn2; mitochondrial permeability transition pore, MPTP; ellagic acid, EA; reactive oxygen species, ROS; peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC1α; NADPH oxidase 1 and 4; NOX1 and NOX4.