Mitochondrial uncoupling downregulates calsequestrin expression and reduces SR Ca2+ stores in cardiomyocytes (original) (raw)
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Abnormal Ca2+ release and catecholamine-induced arrhythmias in mitochondrial cardiomyopathy
Human Molecular Genetics, 2005
Mitochondrial dysfunction is implicated in numerous cardiac disorders. It has been assumed that the functional defects are directly related to a decreased rate of mitochondrial ATP production, but recent studies have challenged this idea. Here, we used mice with tissue-specific knockout of mitochondrial transcription factor A (Tfam) that leads to progressive cardiomyopathy. The role of changes in the excitation-contraction (E-C) coupling in cardiomyocytes of these mice was studied by measuring the free cytosolic Ca 21 concentration and by analyzing the expression of genes encoding E-C coupling proteins. Action potential-mediated Ca 21 transients, measured with the fluorescent indicator fluo-3 in isolated cardiomyocytes, were smaller and faster in Tfam knockout cardiomyocytes when compared with controls. The total sarcoplasmic reticulum (SR) Ca 21 content was decreased in Tfam knockout cells. The gene for the SR Ca 21 binding protein calsequestrin-2 (CASQ2), as well as other genes encoding proteins involved in SR Ca 21 handling, showed decreased expression in Tfam knockout hearts. Decreased CASQ2 levels have been linked to severe arrhythmias triggered by b-adrenergic stimulation. In line with this, application of the b-adrenergic agonist isoproterenol resulted in frequent doublet Ca 21 transients in Tfam knockout cardiomyocytes. In conclusion, our results show that mitochondrial dysfunction in the heart induces specific down-regulation of the expression of genes encoding proteins involved in E-C coupling. These changes predispose to cardiac arrhythmias and terminal heart failure and are thus important in the pathogenesis of mitochondrial cardiomyopathy.
The SR-mitochondria interaction: a new player in cardiac pathophysiology
Cardiovascular Research, 2010
Mitochondria are essential for energy supply and cell signalling and may be triggers and effectors of cell death. Mitochondrial respiration is tightly controlled by the matrix Ca 2+ concentration, which is beat-to-beat regulated by uptake and release mainly through the mitochondrial Ca 2+ uniporter and Na + /Ca 2+ exchanger, respectively. Recent studies demonstrate that mitochondrial Ca 2+ uptake is more dependent on anatomo-functional microdomains established with the sarcoplasmic reticulum (SR) than on cytosolic Ca 2+. This privileged communication between SR and mitochondria is not restricted to Ca 2+ but may involve ATP and reactive oxygen species, which has important implications in cardiac pathophysiology. The disruption of the SR-mitochondria interaction caused by cell remodelling has been implicated in the deterioration of excitation-contraction coupling of the failing heart. The SR-mitochondria interplay has been suggested to be involved in the depressed Ca 2+ transients and mitochondrial dysfunction observed in diabetic hearts as well as in the genesis of certain arrhythmias, and it may play an important role in myocardial reperfusion injury. During reperfusion, re-energization in the presence of cytosolic Ca 2+ overload results in SR-driven Ca 2+ oscillations that may promote mitochondrial permeability transition (MPT). The relationship between MPT and Ca 2+ oscillations is bidirectional, as recent data show that the induction of MPT in Ca 2+-overloaded cardiomyocytes may result in mitochondrial Ca 2+ release that aggravates Ca 2+ handling and favours hypercontracture. A more complete characterization of the structural arrangements responsible for SR-mitochondria interplay will allow better understanding of cardiac (patho)physiology but also, and no less important, should serve as a basis for the development of new treatments for cardiac diseases.
Mitochondrial Ca2+ levels lower down rate of metabolic diseases and cardiomyopathies
Journal of Stem Cell Research & Therapeutics, 2018
Present review article explains role of mitochondria in regulation of calcium metabolism. Besides, combustion of fuel and ATP generation for all physiological and metabolic activities, it regulates Ca 2+ uptake, that is essentially required for intracellular Ca 2+ signaling, cell metabolism cell proliferation and survival. However, buffering of cytosolic Ca 2+ levels regulate mitochondrial effectors. Mitochondria work as a Ca 2+ sink that is formed by electrochemical gradient generated during oxidative phosphorylation, which makes tunneling of the cation an exergonic process. However, excessive calcium influx increases ROS generation and induces mitochondrial depolarization that results in metabolic diseases and evokes cardiomyopathies. In the present article calcium regulated mitochondrial functions have been explained with their wide concern to metabolic defects and cardiac muscle irregularities.
Antioxidants & Redox Signaling, 2011
Aims: Heart disease is commonly associated with altered mitochondrial function and signs of oxidative stress. This study elucidates whether primary cardiac mitochondrial dysfunction causes changes in cardiomyocyte handling of reactive oxygen species (ROS) and Ca 2+. We used a mouse model with a tissue-specific ablation of the recently discovered mtDNA transcription regulator Mterf3 (Mterf3 KO). These mice display a cardiomyopathy with severe respiratory chain dysfunction, cardiac hypertrophy, and shortened lifespan. ROS and Ca 2+ handling were measured using fluorescent indicators and confocal microscopy. Results: Mterf3 KO hearts displayed no signs of increased ROS production or oxidative stress. Surprisingly, Mterf3 KO cardiomyocytes showed enlarged Ca 2+ transient amplitudes, faster sarcoplasmic reticulum (SR) Ca 2+ reuptake, and increased SR Ca 2+ load, resembling increased adrenergic stimulation. Furthermore, spontaneous releases of Ca 2+ were frequent in Mterf3 KO cardiomyocytes. Electrocardiography (measured with telemetry in freely moving mice) showed a terminal state in Mterf3 KO mice with gradually developing bradycardia and atrioventricular block. Conclusion: In conclusion, mitochondrial dysfunction induced by Mterf3 KO leads to a cardiomyopathy without signs of oxidative stress but with increased cardiomyocyte Ca 2+ cycling and an arrhythmogenic phenotype. These findings highlight the complex interaction between mitochondrial function, cardiomyocyte contractility, and compensatory mechanisms, such as activation of adrenergic signaling.
Mitochondrial uncoupling, ROS generation and cardioprotection
Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2018
Mitochondrial oxidative phosphorylation is incompletely coupled, since protons translocated to the intermembrane space by specific respiratory complexes of the electron transport chain can return to the mitochondrial matrix independently of the ATP synthase-a process known as proton leak-generating heat instead of ATP. Proton leak across the inner mitochondrial membrane increases the respiration rate and decreases the electrochemical proton gradient (Δp), and is an important mechanism for energy dissipation that accounts for up to 25% of the basal metabolic rate. It is well established that mitochondrial superoxide production is steeply dependent on Δp in isolated mitochondria and, correspondingly, mitochondrial uncoupling has been identified as a cytoprotective strategy under conditions of oxidative stress, including diabetes, drug-resistance in tumor cells, ischemiareperfusion (IR) injury or aging. Mitochondrial uncoupling proteins (UCPs) are able to lower the efficiency of oxidative phosphorylation and are involved in the control of mitochondrial reactive oxygen species (ROS) production. There is strong evidence that UCP2 and UCP3, the UCP1 homologues expressed in the heart, protect against mitochondrial oxidative damage by reducing the production of ROS. This review first analyzes the relationship between mitochondrial proton leak and ROS generation, and then focuses on the cardioprotective role of chemical uncoupling and uncoupling mediated by UCPs. This includes their protective effects against cardiac IR, a condition known to increase ROS production, and their roles in modulating cardiovascular risk factors such as obesity, diabetes and atherosclerosis.
Mitochondrial Function and Dysfunction in Dilated Cardiomyopathy
Frontiers in Cell and Developmental Biology, 2021
Cardiac tissue requires a persistent production of energy in order to exert its pumping function. Therefore, the maintenance of this function relies on mitochondria that represent the “powerhouse” of all cardiac activities. Mitochondria being one of the key players for the proper functioning of the mammalian heart suggests continual regulation and organization. Mitochondria adapt to cellular energy demands via fusion-fission events and, as a proof-reading ability, undergo mitophagy in cases of abnormalities. Ca2+ fluxes play a pivotal role in regulating all mitochondrial functions, including ATP production, metabolism, oxidative stress balance and apoptosis. Communication between mitochondria and others organelles, especially the sarcoplasmic reticulum is required for optimal function. Consequently, abnormal mitochondrial activity results in decreased energy production leading to pathological conditions. In this review, we will describe how mitochondrial function or dysfunction impa...
In adult cardiomyocytes, T-tubules, junctional sarcoplasmic reticulum (jSR), and mitochondria juxtapose each other and form a unique and highly repetitive functional structure along the cell. The close apposition between jSR and mitochondria creates high Ca 2+ microdomains at the contact sites, increasing the efficiency of the excitation-contraction-bioenergetics coupling, where the Ca 2+ transfer from SR to mitochondria plays a critical role. The SR-mitochondria contacts are established through protein tethers, with mitofusin 2 the most studied SR-mitochondrial "bridge", albeit controversial. Mitochondrial Ca 2+ uptake is further optimized with the mitochondrial Ca 2+ uniporter preferentially localized in the jSR-mitochondria contact sites and the mitochondrial Na + /Ca 2+ exchanger localized away from these sites. Despite all these unique features facilitating the privileged transport of Ca 2+ from SR to mitochondria in adult cardiomyocytes, the question remains whether mitochondrial Ca 2+ concentrations oscillate in synchronicity with cytosolic Ca 2+ transients during heartbeats. Proper Ca 2+ transfer controls not only the process of mitochondrial bioenergetics, but also of mitochondria-mediated cell death, autophagy/mitophagy, mitochondrial fusion/fission dynamics, reactive oxygen species generation, and redox signaling, among others. Our review focuses specifically on Ca 2+ signaling between SR and mitochondria in adult cardiomyocytes. We discuss the physiological and pathological implications of this SR-mitochondrial Ca 2+ signaling, research gaps, and future trends.
Mitochondrial calcium overload is a key determinant in heart failure
We demonstrate that intracellular Ca2+ leak causes mitochondrial Ca2+ overload and dysfunction in postischemic heart failure (HF). In particular, sarcoplasmic reticulum (SR) Ca2+ leak via type 2 ryanodine receptor (RyR2)—but not type 2 inositol 1,4,5-trisphosphate receptor (IP3R2)—channels plays a fundamental role in the pathophysiology of mitochondrial Ca2+ overload and dysfunction in HF. We present here a previously undisclosed molecular mechanism in HF with crucial implications in cardiac physiology. Indeed, our data establish a feedback loop between SR and mitochondria in which SR Ca2+ leak triggers mitochondrial dysfunction and increases the production of free radicals, which in turn lead to posttranslational modifications of RyR2 and enhance intracellular Ca2+ leak, thereby contributing to impaired cardiac function after myocardial infarction.