Mitochondria and oxidative stress in heart aging

As average lifespan of humans increases in western countries, cardiac diseases become the first cause of death. Aging is among the most important risk factors that increase susceptibility for developing cardiovascular diseases. The heart has very aerobic metabolism, and is highly dependent on mitochondrial function, since mitochondria generate more than 90 % of the intracellular ATP consumed by cardiomyocytes. In the last few decades, several investigations have supported the relevance of mitochondria and oxidative stress both in heart aging and in the development of cardiac diseases such as heart failure, cardiac hypertrophy, and diabetic cardiomyopathy. In the current review, we compile different studies corroborating this role. Increased mitochondria DNA instability, impaired bioenergetic efficiency, enhanced apoptosis, and inflammation processes are some of the events related to mitochondria that occur in aging heart, leading to reduced cellular survival and cardiac dysfunction. Knowing the mitochondrial mechanisms involved in the aging process will provide a better understanding of them and allow finding approaches to more efficiently improve this process.     

The mitochondrial organelle and the heart

The heart is highly dependent for its function on oxidative energy generated in mitochondria, primarily by fatty acid beta-oxidation, respiratory electron chain and oxidative phosphorylation. Defects in mitochondrial structure and function have been found in association with cardiovascular diseases such as dilated and hypertrophy cardiomyopathy, cardiac conduction defects and sudden death, ischemic and alcoholic cardiomyopathy, as well as myocarditis. While a subset of these mitochondrial abnormalities have a defined genetic basis (e.g. mitochondrial DNA changes leading to oxidative phosphorylation dysfunction,fatty acid beta-oxidation defects due to specific nuclear DNA mutations), other abnormalities appear to be due to a more sporadic or environmental cardiotoxic insult or have not yet been characterized.This review focuses on abnormalities in mitochondrial bioenergetic function and mitochondrial DNA defects associated with cardiovascular diseases, their significance in cardiac pathogenesis as well as on the available diagnostic and therapeutic options. A concise background concerning mitochondrial biogenesis and bioenergetic pathways during cardiac growth,development and aging will also be provided.     

Mitochondrial tolerance to stress impaired in failing heart

Mitochondrial integrity is critical in the maintenance of bioenergetic homeostasis of the myocardium, with oxidative or metabolic challenge to mitochondria precipitating cell injury. In heart failure, where cardiac cells are exposed to elevated stress, mitochondrial vulnerability could contribute to the disease state. However, the mitochondrial response to stress is yet to be established in heart failure. Here, mitochondrial function and structure was evaluated prior and following stress using a transgenic (TG) model of heart failure, generated by cardiac overexpression of the cytokine TNFalpha. Compared to the wild type, mitochondria from TG failing hearts demonstrated impaired oxidative phosphorylation, mitochondrial DNA damage, reduced mitochondrial creatine kinase activity, abnormal calcium handling, and altered ultrastructure. Under anoxia/reoxygenation or calcium stress, mitochondria from failing hearts suffered exacerbated energetic failure with pronounced cytochrome c release. Thus, mitochondria from TNFalpha-TG failing hearts demonstrate structural and functional abnormalities, with reduced tolerance to stress manifested by impaired bioenergetics and increased susceptibility to injury. This abnormal vulnerability to stress underscores the impact of mitochondrial dysfunction in the pathobiology of heart failure.     

Understanding the impact of mitochondrial defects in cardiovascular disease: a review

OBJECTIVE: Defects in mitochondrial structure and function have been found in association with cardiovascular diseases such as dilated and hypertrophic cardiomyopathy, cardiac conduction defects and sudden death, ischemic and alcoholic cardiomyopathy, and myocarditis. A genetic basis has been established for some mitochondrial abnormalities (eg, mitochondrial DNA changes leading to oxidative phosphorylation dysfunction, fatty acid beta-oxidation (FAO) defects resulting from specific nuclear mutations) whereas other abnormalities appear to be due to a more sporadic or environmental cardiotoxic insult or have not yet been characterized. METHODS: This article reviews mitochondrial abnormalities in structure or function reported in cardiac diseases highlighting information about their potential etiology, significance in cardiac pathogenesis, and diagnostic and therapeutic options available to the clinician. We also provide a brief background concerning mitochondrial biogenesis and bioenergetic pathways in cardiac growth, development, and aging. CONCLUSIONS: Although aberrations in bioenergetic functioning of mitochondria appear to be most often related to cardiac dysfunction, the primary defect(s) causing bioenergetic dysfunction may reside in a nonbioenergetic pathway (eg, signaling between mitochondria and nucleus) or in overall mitochondrial biogenesis or degradation pathways.     

Age-dependent mitochondrial energy dynamics in the mice heart: Role of superoxide dismutase-2

The aging process alters cardiac physiology, decreases the number of cardiomyocytes and alters the energy metabolism. Mitochondrial dysfunction in aging is believed to cause these functional and phenotypic changes in the heart. Although precise understanding of alterations of mitochondrial respiration in aging is necessary to manage heart diseases in the elderly population conflicting data on the function of specific complex of electron transport chain of the heart mitochondria limits the intervention process. We have addressed these issues using the assay of mitochondrial coupling and electron flow to assess specific functional defects in mitochondria isolated from young or aged mice. Our results demonstrate that cardiac mitochondria from older mice utilize oxygen at a decreased rate via complex I, II or IV compared to younger mice. We further show that mitochondrial function decreases in young Sod2^+/− mice heart compared to young wildtype mice. However, the mitochondrial function remains unchanged in older Sod2^+/− mice heart compared to younger Sod2^+/− mice heart. Further, the oxygen consumption remains similar in old wildtype mice and old Sod2^+/− mice heart mitochondria. The expression and activity of Sod2 in young or old Sod2^+/− mice heart remain unchanged. These data demonstrate that decreased oxygen utilization in older age could have resulted in decreased mitochondrial ROS-mediated oxidative damage requiring less Sod2 for protection against mitochondrial oxidative stress in older wildtype or older Sod2^+/− mice.     

Constitutive SIRT1 overexpression impairs mitochondria and reduces cardiac function in mice

Heart failure is associated with a change in cardiac energy metabolism. SIRT1 is a NAD⁺-dependent protein deacetylase, and important in the regulation of cellular energy metabolism. To examine the role of SIRT1 in cardiac energy metabolism, we created transgenic mice overexpressing SIRT1 in a cardiac-specific manner, and investigated cardiac functional reserve, energy reserve, substrate uptake, and markers of mitochondrial function. High overexpression of SIRT1 caused dilated cardiomyopathy. Moderate overexpression of SIRT1 impaired cardiac diastolic function, but did not cause heart failure. Fatty acid uptake was decreased and the number of degenerated mitochondria was increased dependent on SIRT1 gene dosage. Markers of reactive oxygen species were decreased. Changes in morphology and reactive oxygen species were associated with the reduced expression of genes related to mitochondrial function and autophagy. In addition, the respiration of isolated mitochondria was decreased. Cardiac function was normal in transgenic mice expressing a low level of SIRT1 at baseline, but the mice developed cardiac dysfunction upon pressure overload. In summary, the constitutive overexpression of SIRT1 reduced cardiac function associated with impaired mitochondria in mice.     

Metabolic disorders of cardiac muscle in alcoholic and smoke cardiomyopathy

The acute and prolonged effects of alcohol and smoking on the oxidative and energy processes of cardiac muscle in experimental animals were studied at the subcellular level. The acute effect of alcohol manifested itself by decreasing mitochondrial respiration, compensated by increased glycolytic activity of the myocardium so that myocardial energy phosphate concentration remained unchanged. The prolonged effect of alcohol (for a period of 14 days) resulted in a decrease in oxidative processes as well as in glycolytic activity with a subsequent decline in myocardial ATP and CP levels. Smoking led to a significant decrease in oxidative and total bioenergetic processes of cardiac muscle mitochondria both after acute and prolonged smoking. This metabolic disorder is localized in the terminal segment of the respiratory chain of the mitochondria at the level of cytochrome oxidase. The authors conclude that the above-mentioned disorders may play a role in the development of heart failure on the basis of alcoholic or smoke cardiomyopathy.     

Mouse models of mitochondrial dysfunction and heart failure

Mitochondria in the adult mammalian heart have a tremendous capacity for oxidative metabolism, and the conversion of energy by these pathways is critical for proper cardiac function. This review describes mouse models relating mitochondrial metabolism to cardiac function through gain- or loss-of-function approaches that manipulate mitochondrial energy transduction or ATP synthetic pathways. Mouse models of mitochondrial defects are relevant to genetic and acquired forms of human cardiomyopathy. Examples include inborn errors in mitochondrial metabolism or end-stage heart failure. Conversely, chronic reliance on energy production via mitochondrial fatty acid oxidation, such as occurs in the diabetic heart, likely leads to maladaptive sequelae including cellular lipotoxicity and mitochondrial dysfunction. Collectively, these model systems have allowed us to begin to dissect the relationship between mitochondrial metabolism and the development of cardiomyopathy and to define the molecular pathways regulating cardiac mitochondrial number and function.     

Mitochondrial dysfunction in cardiac disease: ischemia--reperfusion, aging, and heart failure.

Mitochondria contribute to cardiac dysfunction and myocyte injury via a loss of metabolic capacity and by the production and release of toxic products. This article discusses aspects of mitochondrial structure and metabolism that are pertinent to the role of mitochondria in cardiac disease. Generalized mechanisms of mitochondrial-derived myocyte injury are also discussed, as are the strengths and weaknesses of experimental models used to study the contribution of mitochondria to cardiac injury. Finally, the involvement of mitochondria in the pathogenesis of specific cardiac disease states (ischemia, reperfusion, aging, ischemic preconditioning, and cardiomyopathy) is addressed.     

Cardiological manifestations of mitochondrial respiratory chain disorders

Mitochondrial Respiratory Chain Disorders (MRCD) are a heterogeneous group of disorders that share the involvement of the cellular bioenergetic machinery due to molecular defects affecting the mitochondrial oxidative phosphorylation system (OXPHOS).Clinically, they usually involve multiple tissues although they tend to mainly affect nervous system and skeletal muscle. Cardiological manifestations are frequent and include hypertrophic or dilated cardiomyopathies and heart conduction defects, being part of adult or infantile multisystemic mitochondrial disorders or, less frequently, presenting as isolated clinical condition.The aim of this review is to update the cardiological manifestations in both adult and infantile mitochondrial disorders going briefly over mitochondrial genetics.Cardiac involvement is a common feature associated with early and late onset forms of MRCD. In particular cases, these conditions should be considered into the diagnostic algorithm of idiopathic cardiomyopathies. Physicians strictly related with this disorders need to be aware of heart complications and therefore periodical cardiological examinations should be performed in such patients. Finally, therapeutic strategies are suggested to treat cardiac disorders in MRCDKey words: Mitochondrial cardiomyopathies, molecular diagnosis, therapy     

Hepato-cardiac disorders

Understanding the mutual relationship between the liver and the heart is important for both hepatologists and cardiologists. Hepato-cardiac diseases can be classified into heart diseases affecting the liver, liver diseases affecting the heart, and conditions affecting the heart and the liver at the same time. Differential diagnoses of liver injury are extremely important in a cardiologist's clinical practice calling for collaboration between cardiologists and hepatologists due to the many other diseases that can affect the liver and mimic haemodynamic injury. Acute and chronic heart failure may lead to acute ischemic hepatitis or chronic congestive hepatopathy. Treatment in these cases should be directed to the primary heart disease. In patients with advanced liver disease, cirrhotic cardiomyopathy may develop including hemodynamic changes, diastolic and systolic dysfunctions, reduced cardiac performance and electrophysiological abnormalities. Cardiac evaluation is important for patients with liver diseases especially before and after liver transplantation. Liver transplantation may lead to the improvement of all cardiac changes and the reversal of cirrhotic cardiomyopathy. There are systemic diseases that may affect both the liver and the heart concomitantly including congenital, metabolic and inflammatory diseases as well as alcoholism. This review highlights these hepatocardiac diseases     

病毒性心肌病小鼠心肌线粒体基因表达变化

目的观察实验性病毒性心肌病小鼠心肌线粒体基因表达变化情况,探讨线粒体基因表达变化在病毒性心肌病中的发病作用。方法用柯萨奇病毒B3m反复增量感染Balb/c小鼠,建立心肌病动物模型,用包容35 852条基因的cDNA微矩阵芯片分析心脏组织特异的mRNA表达,筛选出明显差异表达的线粒体相关基因。采用原位末端脱氧核糖核苷酸转移酶介导的dUTP缺口末端标记法(TUNEL)观察心肌细胞凋亡情况。结果共有31个心肌病小鼠心肌线粒体能量代谢相关基因、心肌细胞线粒体凋亡及相关调节基因明显差异表达。心肌病小鼠心肌细胞凋亡的数目明显高于对照组(t=8.85,P<0.01)。结论心肌线粒体功能受损伴有心肌细胞凋亡发生是病毒性心肌病的重要发病机制。     

线粒体质量控制与围生期心脏发育的相关研究进展

心脏作为哺乳动物能量消耗最高的器官之一,其在围生期发育过程中需要完成从无氧糖酵解到脂肪酸氧化的能量代谢转换,期间心肌细胞线粒体发育迅速,以满足心脏对能量的需要。近年来研究发现线粒体质量控制在围生期心脏发育成熟过程中发挥重要作用。线粒体质量控制包括线粒体生物合成、线粒体融合/分裂以及线粒体自噬等过程,通过维持线粒体结构及功能的完整来保证细胞功能及代谢的正常。本文就哺乳类动物心脏发育过程中线粒体质量控制系统的变化及其在心脏发育中的作用进行综述。     

Hepato-cardiac disorders简

Understanding the mutual relationship between the liver and the heart is important for both hepatologists and cardiologists. Hepato-cardiac diseases can be classified into heart diseases affecting the liver, liver diseases affecting the heart, and conditions affecting the heart and the liver at the same time. Differential diagnoses of liver injury are extremely important in a cardiologist’s clinical practice calling for collaboration between cardiologists and hepatologists due to the many other diseases that can affect the liver and mimic haemodynamic injury. Acute and chronic heart failure may lead to acute ischemic hepatitis or chronic congestive hepatopathy. Treatment in these cases should be directed to the primary heart disease. In patients with advanced liver disease, cirrhotic cardiomyopathy may develop including hemodynamic changes, diastolic and systolic dysfunctions, reduced cardiac performance and electrophysiological abnormalities. Cardiac evaluation is important for patients with liver diseases especially before and after liver transplantation. Liver transplantation may lead to the improvement of all cardiac changes and the reversal of cirrhotic cardiomyopathy. There are systemic diseases that may affect both the liver and the heart concomitantly including congenital, metabolic and inflammatory diseases as well as alcoholism. This review highlights these hepatocardiac diseases     

SENP5, a SUMO isopeptidase,induces apoptosis and cardiomyopathy

Cardiomyopathy presents a major health issue and is a leading cause of heart failure. Although a subset of familial cardiomyopathy is associated with genetic mutations, over 50% of cardiomyopathy is defined as idiopathic, the mechanisms underlying which are under intensive investigation. SUMO conjugation is a dynamic posttranslational modification that can be readily reversed by the activity of sentrin-specific proteases (SENPs). However, whether SENPs are implicated in heart disease pathophysiology remains unexplored. We observed a significant increase in the level of SENP5, a SUMO isopeptidase, in human idiopathic failing hearts. To reveal whether it plays a role in the pathogenesis of cardiac muscle disorders, we used a gain-of-function approach to overexpress SENP5 in murine cardiomyocytes (SENP5 transgenic, SENP5-Tg). Overexpression of SENP5 led to cardiac dysfunction, accompanied by decreased cardiomyocyte proliferation and elevated apoptosis. The increase in apoptosis preceded other detectable pathological changes, suggesting its causal link to cardiomyopathy. Further examination of SENP5-Tg hearts unveiled a decrease in SUMO attachment to dynamin related protein (Drp1), a factor critical for mitochondrial fission. Correspondingly, the mitochondria of SENP5-Tg hearts at an early developmental stage were significantly larger compared with those in the control hearts, suggesting that desumoylation of Drp1 at least partially accounts for the cardiac phenotypes observed in the SENP5-Tg mice. Finally, overexpression of Bcl2 in SENP5-Tg hearts improved cardiac function of SENP5-Tg mice, further supporting the notion that SENP5 mainly targets mitochondrial function in vivo. Our findings demonstrate an important role of the desumoylation enzyme SENP5 in the development of cardiac muscle disorders, and point to the SUMO conjugation pathway as a potential target in the prevention/treatment of cardiomyopathy. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease".     

Mechanisms of isoproterenol‐induced cardiac mitochondrial damage: protective actions of melatonin

Mitochondrial dysfunction due to oxidative damage is the key feature of several diseases. We have earlier reported mitochondrial damage resulting from the generation of oxidative stress as a major pathophysiological effect of isoproterenol (ISO)‐induced myocardial ischemia in rats. That melatonin is an antioxidant that ameliorates oxidative stress in experimental animals as well as in humans is well established. We previously demonstrated that melatonin provides cardioprotection against ISO‐induced myocardial injury as a result of its antioxidant properties. The mechanism of ISO‐induced cardiac mitochondrial damage and protection by melatonin, however, remains to be elucidated in vitro. In this study, we provide evidence that ISO causes dysfunction of isolated goat heart mitochondria. Incubation of cardiac mitochondria with increasing concentrations of ISO decreased mitochondrial succinate dehydrogenase (SDH) activity, which plays a pivotal role in mitochondrial bioenergetics, as well as altered the activities of other key enzymes of the Kreb's cycle and the respiratory chain. Co‐incubation of ISO‐challenged mitochondria with melatonin prevented the alterations in enzyme activity. That these changes in mitochondrial energy metabolism were due to the perpetration of oxidative stress by ISO was evident from the increased levels of lipid peroxidation and decreased reduced glutathione/oxidized glutathione ratio. ISO‐induced oxidative stress also altered mitochondrial redox potential and brought about changes in the activity of the antioxidant enzymes manganese superoxide dismutase and glutathione peroxidase, eventually leading to alterations in total ATPase activity and membrane potential. Melatonin ameliorated these changes likely through its antioxidant abilities suggesting a possible mechanism of cardioprotection by this indole against ISO‐induced myocardial injury.     

Mitochondrial-Shaping Proteins in Cardiac Health and Disease – the Long and the Short of It!

Mitochondrial health is critically dependent on the ability of mitochondria to undergo changes in mitochondrial morphology, a process which is regulated by mitochondrial shaping proteins. Mitochondria undergo fission to generate fragmented discrete organelles, a process which is mediated by the mitochondrial fission proteins (Drp1, hFIS1, Mff and MiD49/51), and is required for cell division, and to remove damaged mitochondria by mitophagy. Mitochondria undergo fusion to form elongated interconnected networks, a process which is orchestrated by the mitochondrial fusion proteins (Mfn1, Mfn2 and OPA1), and which enables the replenishment of damaged mitochondrial DNA. In the adult heart, mitochondria are relatively static, are constrained in their movement, and are characteristically arranged into 3 distinct subpopulations based on their locality and function (subsarcolemmal, myofibrillar, and perinuclear). Although the mitochondria are arranged differently, emerging data supports a role for the mitochondrial shaping proteins in cardiac health and disease. Interestingly, in the adult heart, it appears that the pleiotropic effects of the mitochondrial fusion proteins, Mfn2 (endoplasmic reticulum-tethering, mitophagy) and OPA1 (cristae remodeling, regulation of apoptosis, and energy production) may play more important roles than their pro-fusion effects. In this review article, we provide an overview of the mitochondrial fusion and fission proteins in the adult heart, and highlight their roles as novel therapeutic targets for treating cardiac disease.     

A time to reap,a time to sow: Mitophagy and biogenesis in cardiac pathophysiology

Balancing mitophagy and mitochondrial biogenesis is essential for maintaining a healthy population of mitochondria and cellular homeostasis. Coordinated interplay between these two forces that govern mitochondrial turnover plays an important role as an adaptive response against various cellular stresses that can compromise cell survival. Failure to maintain the critical balance between mitophagy and mitochondrial biogenesis or homeostatic turnover of mitochondria results in a population of dysfunctional mitochondria that contribute to various disease processes. In this review we outline the mechanics and relationships between mitophagy and mitochondrial biogenesis, and discuss the implications of a disrupted balance between these two forces, with an emphasis on cardiac physiology. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease".     

类风湿性关节炎的心血管损害

类风湿性关节炎合并心脏损害并非少见,包括心包炎、心肌病/心肌炎、心脏淀粉样变性、瓣膜病、冠状动脉血管炎、心律失常以及充血性心力衰竭和缺血性心脏病,尤其是后二者明显增加了类风湿性关节炎的死亡率。心脏病学家应该和风湿病学家共同努力,降低类风湿性关节炎合并心血管疾病的死亡率。     

Oxidative phosphorylation and respiration by mitochondria from normal, hypertrophied and failing rat hearts.

The present study was undertaken in order to determine the differences in mitochondrial respiration and oxidative phosphorylation of the myocardium from rats with monocrotaline pyrrole induced pulmonary heart disease. Experimental animals developed right ventricular hypertrophy and heart failure 6 weeks post monocrotaline pyrrole injection. Respiratory function of heart mitochondria in glutamate and succinate substrates was evaluated polarographically. Mitochondrial electron transport and phosphorylating efficiency increased slightly during cardiac hypertrophy, began to decline during impending cardiac failure, and was markedly impaired in congestive heart failure.