Editorial: Mitochondrial Dysfunction and Cardiovascular Diseases

Abstract

Editorial on the Research Topic Mitochondrial Dysfunction and Cardiovascular Diseases A deeper understanding of the molecular mechanisms underlying the development and progression of cardiovascular diseases represents a major goal in cardiovascular medicine. Mitochondrial dysfunction has emerged as major player in the development of cardiovascular diseases, with potential therapeutic implications. Mitochondrial dysfunction encompasses mitochondrial complex disruption, mitochondrial uncoupling, and cristae remodeling and swelling, which in turn cause ROS accumulation, energy stress, and cell death. This Research Topic is a collection of original and state-of-the art review articles discussing and extending our current knowledge about molecular mechanisms responsible for mitochondrial dysfunction in cardiovascular diseases. Many aspects of mitochondrial biology and therapies targeting damaged mitochondria have been highlighted. One of the main feature of mitochondrial dysfunction observed in several cardiovascular diseases is the exaggerated generation of mitochondrial ROS (1), which represents the common pathological substrate underlying diabetes-induced complications, such as cardiomyopathy, as comprehensively described by Kaludercic and Di Lisa in their review article. Mitochondrial ROS are generated from multiple sources in cardiomyocytes during diabetes by a feed-forward/amplification mechanism, which further exacerbates oxidative stress and causes contractile dysfunction. The authors reviewed current therapies aimed at reducing ROS and improving cardiac function in diabetic patients. While some systemic antioxidants failed to exert cardiac protection in clinical trials, mitochondrial-targeted antioxidants such as MitoTEMPO were shown to be cardioprotective in preclinical models of diabetic cardiomyopathy. Sodium glucose cotransporter 2 (SGLT2) inhibitors also appear to be promising drugs to reduce cardiovascular events in diabetic patients. In this regard, Maejima provided a detailed overview about the mitochondrial-mediated mechanisms underlying the beneficial effects of SGLT2 inhibitors in heart failure. SGLT2 inhibitors increase ketone bodies, which represent a suitable source of energy in failing hearts, and also improve sodium metabolism and mitochondrial dynamics. However, further studies are needed to identify other targets modulated by SGLT2 inhibitors, since SGLT2 does not appear to be expressed in human and rodent cardiomyocytes, at least in unstressed conditions. A modulation of mitochondrial dynamics may contribute to the beneficial effects of this class of drugs on mitochondrial function in response to metabolic derangements (2). Targeting mitochondria, and in particular mitochondrial ROS, has also emerged as a potential therapy for patients with dilated cardiomyopathy with ataxia syndrome (DCMA), a rare genetic disorder caused by a mutation of DNAJ Heat Shock Protein Family (Hsp40) Member C19 (DNAJC19), a protein localized in the inner mitochondrial membrane. Machiraju et al. demonstrated that SS-31, a mitochondrial targeted antioxidant, also known as elamipretide or Bendavia, rescues mitochondrial fragmentation, oxidative stress, and improves mitochondrial fusion in skin fibroblasts extracted from DCMA patients. However, the therapeutic potential of SS-31 in improving cardiac function in patients with DCMA should be assessed in further studies. Mitochondrial health is facilitated by specific quality control mechanisms, such as mitophagy, a cargo-specific form of autophagy selective for elimination of damaged mitochondria (3). Damaged mitochondria are degraded by mitophagy and defects in mitophagy were reported to lead to harmful cardiovascular effects, because of accumulation of defective mitochondria. In their original article, Thomas et al. found decreased levels of Parkin protein in the heart of obese mice. Parkin is a ubiquitin E3 ligase, which represents a canonical regulator of mitophagy and proteasome degradation. The authors also observed a modest increase of infarct size in obese mice undergoing ischemia/reperfusion (IR) ex-vivo and a cardiac accumulation of ubiquitinated mitochondrial proteins at baseline and in response to IR in obese animals. This study suggested that mitophagy may be impaired in the context of obesity because of Parkin downregulation, thereby predisposing the heart to develop increased injury in response to stress. However, a direct assessment of mitophagy was not performed in this study and further work is necessary to clarify the impact of metabolic alterations on Parkin-dependent and independent mitophagy in the heart. The importance of autophagy and mitophagy abnormalities in aging-induced cardiovascular abnormalities was the main focus of the review article by Liang and Gustafsson. The authors reviewed relevant literature supporting the concept that autophagy declines with aging, leading to age-related cardiovascular diseases, due to alterations in cellular energy metabolism and adaption to stress. Either genetic or pharmacological activation of mitophagy appears to attenuate aging-related abnormalities, whereas its inhibition seems to accelerate them (4). It will be important to understand in the future how aging affects Parkin-dependent and independent mitophagy in the heart, and the exact molecular mechanisms through which autophagosome formation and fusion are impaired by the aging process. Increased oxidative stress and inflammation appear to play a critical role. Aside from mitophagy and mitochondrial dynamics, mitochondrial proteostasis is also emerging as an important mechanism regulating mitochondrial quality control in the heart, as described in the paper by Arrieta et al. Mitochondrial proteostasis regulates biogenesis, folding, and degradation of mitochondrial proteins and this process appears to be altered during cardiac stress. In the presence of misfolded protein...