Involvement of Oxidative Stress in Mitochondrial Abnormalities During the Development of Heart Disease

1. Introduction

Oxidative stress and intracellular Ca²⁺-overload are intimately involved in different cardiac pathologies including heart failure, diabetic cardiomyopathy and ischemia-reperfusion injury [1,2,3,4,5,6,7]. Such defects in cardiomyocyte Ca²⁺-handling have been attributed to subcellular remodeling during the development of heart disease [8,9,10,11,12,13,14]. Mitochondria are the major source of ATP production through oxidative phosphorylation and electron transport required for cardiac function [15,16,17,18] and are regarded as multifunctional organelles involved in cardiomyocyte function and integrity. Indeed, mitochondria regulate key processes including mitophagy, apoptosis, redox balance and Ca²⁺-homeostasis [19,20,21,22,23,24]. There is unequivocal evidence that mitochondria are a high source of reactive oxygen species (ROS), such as superoxide and hydroxyl radicals as well as the oxidant, H₂O₂, which promote lipid peroxidation leading to a dysregulation of cation homeostasis, cellular damage and cell death [25,26]. In addition, the excessive production of ROS can lead to an accumulation of 4-hydroxynonenal inside the mitochondria, which is a product of lipid peroxidation and reactive aldehyde, and is far more harmful than ROS [27]. Furthermore, the occurrence of oxidative stress that is accompanied by a depletion of antioxidant enzymes and other redox-regulating molecules, which exacerbates the imbalance between ROS generation and detoxification, contributing to the acceleration of myocardial abnormalities in structure and function.

Mitochondria are known to accumulate a considerable amount of Ca²⁺ and thus are considered as a Ca²⁺ reservoir/sink designed to maintain the intracellular concentration of free Ca²⁺ ([Ca²⁺]i) within optimal range [15,16,28]. However, during the development of different cardiac diseases, an excessive amount of intracellular Ca²⁺ results in mitochondria Ca²⁺-overload that subsequently harms mitochondrial energy production [15,16,29]. Taken together, it can be seen from Figure 1 that mitochondrial dysfunction in different types of heart disease and pathophysiological conditions is a key component in the pathogenesis of cardiac dysfunction. This functional decline of the heart is strongly associated with excessive ROS generation, which originates from multiple sources, including NADPH oxidase, monoamine oxidase, and mitochondrial respiratory complexes I, II, and III. Notably, NADPH oxidase 4 (NOX4) has been identified to be present in mitochondria mainly and serves as a principal driver of oxidative stress in heart failure [30]. Figure 2 summarizes the alterations in mitochondrial ROS generating systems.

It should be mentioned that endothelium-associated xanthine oxidase (XO), which is known to generate superoxide anion, is activated by angiotensin II and NADPH oxidase activity in endothelial cells [31]. This surplus of superoxide anions generated through these pathways induces widespread damage to cellular macromolecules, including DNA, proteins, lipids, and carbohydrates, ultimately resulting in mitochondrial dysfunction and irreversible cytotoxicity [32]. Indeed, the interplay between ROS and mitochondrial components creates a self-amplifying cycle of oxidative damage, further exacerbating mitochondrial dysfunction, contractile impairment and overall progression of heart failure [33,34].

Oxidative stress represents a state of redox disequilibrium characterized by the excessive generation of ROS, including superoxide radicals, hydrogen peroxide, and hydroxyl radicals, alongside a concurrent reduction in endogenous antioxidant capacity [35]. The accumulation of mitochondrial ROS accompanied with a variety of different factors including heightened inflammatory response, formation of advanced glycation end-products and lipid peroxidation all collectively exacerbate oxidative stress (Figure 3).

The deleterious effects of oxidative stress are not limited to mitochondrial impairment, but also contribute to the pathological remodeling of the myocardium through the upregulation of pro-inflammatory cytokines and activation of fibroblasts in the extracellular matrix [36,37]. These mechanisms collectively drive interstitial fibrosis and increased myocardial stiffness, which are hallmarks of heart failure progression. It should be mentioned that Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that regulates antioxidant responses and plays a critical role in cellular defense against oxidative stress, inflammation, and apoptosis. It is a key regulator of several genes for several endogenous antioxidants such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase, which are involved in protecting against the development of oxidative damage and mitochondrial dysfunction, making it a promising therapeutic target in cardiovascular diseases [38]. In fact, numerous studies suggest that Nrf2 activation is a crucial cardioprotective mechanism against the adverse effects of ischemic myocardial injury.

The prolonged exposure of the heart to high levels of circulating vasoactive hormones including angiotensin II and catecholamines in chronic myocardial infarction have been shown to induce Ca²⁺-handling abnormalities that have been linked to the occurrence of mitochondrial Ca²⁺-overload, mitochondrial dysfunction, and the generation of oxidative stress all leading to an impairment of cardiovascular function [39,40,41]. Both Ca²⁺ and oxidative stress are considered to induce conformational alterations in the mitochondrial cristae embedded F1/F0, ATP synthase and permit the formation of membrane permeability transition pores (MPTP) for releasing solutes and proteins, including cytochrome C, apoptosis-inducing factor and Smac/DIABLO, from the mitochondrial matrix [42,43,44]. If the MPTP remains in the open state, the cardiomyocyte is unable to sustain its ATP levels ultimately leading to mitochondrial stress, cell death and cardiac dysfunction [45].

Taken together, Figure 4 demonstrates the critical role of mitochondria in alterations in cardiomyocyte structure and function through modulating energy metabolism, formation of the MPTP and inducing apoptotic signals. In view of the importance of mitochondria in normal cell function, this narrative review is intended to describe the role of defects in mitochondrial energy generation, increased ROS production, dysregulation of Ca²⁺-handling and mitochondrial Ca²⁺overlaod as well as cell apoptosis in cardiac dysfunction in different pathophysiological conditions such as heart failure, diabetic cardiomyopathy and ischemia-reperfusion injury. Accordingly, appropriate literature searched on MEDLINE via PubMed by using the search terms: mitochondrial dysfunction, cardiac ischemia-reperfusion injury, diabetic cardiomyopathy, heart failure, reactive oxygen species, oxidative stress, Ca²⁺-handling, intracellular Ca²⁺-overload and combination thereof was conducted and the articles cited in this review were those selected to provide support of our hypothesis.

2. Evidence of Involvement of ROS and Ca²⁺-Overload in Cardiac Mitochondria

Mitochondria play a pivotal role in cellular redox signaling by generating ROS as by-products of oxidative phosphorylation [46,47,48]. However, not all oxidants have a role in signal transduction as it appears that this is dependent upon the cell type and animal species. Furthermore, low concentrations of oxidants or exposure for a transient period stimulate the signal transduction mechanisms for both cardiomyocyte function and gene expression for cell survival, while high concentrations of oxidants and/or exposure for a prolonged period of time produces oxidative stress and subsequent harmful outcomes [8,49].

Figure 4. Mitochondrial abnormalities due to oxidative stress leading changes in cardiac function and structure.

Figure 4. Mitochondrial abnormalities due to oxidative stress leading changes in cardiac function and structure.

The impairment of mitochondrial function by ROS generating systems and oxidants has been reported [50,51]. In this regard, normal rat hearts perfused with an ROS generating system, xanthine (X) plus xanthine oxidase (XO) has been shown to decrease mitochondrial state 3, uncoupled respiration and ADP-to-O ratio without any changes in the state 4 respiration (Figure 5). On the other hand, perfusion with a well known oxidant, H₂O₂ increased mitochondrial state 4 respiration and decreased the ADP-to-O ratio as well as mitochondrial state 3 and uncoupled respiration (Figure 5) [50]. The role of ROS and oxidants in mitochondrial impairment of oxidative stress was further demonstrated by the observations that the changes in mitochondrial function due to X plus XO were attenuated or prevented by the presence of SOD plus CAT, whereas those by H₂O₂ were attenuated by the presence of CAT plus mannitol, but not by CAT alone (Table 1) [50]. The impact of oxidant effect on [Ca²⁺]i is demonstrated by the data presented in Table 2. It was observed that the H2O2-induced increase in [Ca²⁺]i is concentration dependent (Table 2A) [51]. In contrast, incubation of cardiomyocytes with CAT before exposure to H₂O₂ attenuated the H₂O₂-induced increase in [Ca²⁺]i . It should be noted that mannitol did not exert any effect on the H₂O₂-induced increase in [Ca²⁺]i (Table 2B) [51]. Taken together, it can be inferred that the formation of H₂O₂ in different cardiac pathologies can induce changes in Ca²⁺-homeostasis in cardiomyocytes and induce cardiac contractile dysfunction.

3. Development of Mitochondrial Ca²⁺-Overload due to Oxidative Stress

Mitochondria participate in I/R-injury due to oxidative stress and dysregulation of Ca²⁺-homeostasis [52]. In addition, following I/R, cardiomyocytes accumulate high levels of peroxides, leading to mitochondrial dysfunction and induction of ferroptosis and exacerbation of ROS production and oxidative stress [53]. The oxidative stress induced abnormalities in Ca²⁺-handling are known to lead to mitochondrial Ca²⁺-overload resulting in impaired mitochondrial production of energy [54,55,56]. Interestingly, mitochondrial ATPase inhibitory factor-1, which is increased under conditions of oxidative stress has been reported to disturb mitochondrial Ca²⁺-handling; however, the loss of mitochondrial Ca²⁺ uniporter (mCUP) has been reported to trigger arrhythmias attributed to a probable effect on SR Ca²⁺-handling [57,58]. Interestingly, in I/R-injury, Ca²⁺-influx in to mitochondria is considered to occur through the mCUP; however, deletion of the mCUP has been reported to result in an increase in mitochondrial Ca²⁺, suggesting that some other mechanism may also be involved in Ca²⁺-influx [59]. It should also be mentioned that a defect in the cross talk between mitochondrial function and control of ryanodine-receptor-mediated SR Ca²⁺-release has been linked to an increase in the risk of arrhythmia in heart disease [60]. Clearly, targeting Ca²⁺-homeostasis in cardiomyocytes and mitochondrial Ca²⁺-overload due to oxidative stress would be seen as beneficial in attenuating calcium dysregulation in heart disease, including myocardial infarction, heart failure and cardiomyopathies [61].

The sensitivity of mitochondria to Ca²⁺ concentrations is critical, as both excessive and deficient Ca²⁺ levels can impair mitochondrial oxidative phosphorylation. High-glucose conditions in cardiomyocytes have been shown to reduce mCUP expression, decrease mitochondrial Ca²⁺ levels, and alter glucose and lipid metabolic profiles, further compromising cardiac function [62]. Mitochondrial Ca²⁺-overload, in turn, contributes to oxidative stress, which exacerbates mitochondrial dysfunction and creates a vicious cycle of cellular injury. This cascade ultimately leads to apoptosis or necrosis, further impairing both systolic and diastolic heart function [63]. In the context of diabetic cardiomyopathy, the role of mCUP and its regulatory subunit, mitochondrial calcium uptake protein 1 (MICU1), has emerged as a critical factor in Ca²⁺-transport. It has been shown that in diabetic mice, there is an upregulation of MICU1 expression in the heart, accompanied by a downregulation of MCU and associated regulatory proteins, such as EMRE, a key mCUP subunit. This imbalance leads to compromised mitochondrial Ca²⁺- uptake, diminished mitochondrial function, and consequently reduced cardiac performance.

Mitochondria Ca²⁺ accumulation serves as a key trigger of mitochondrial dysfunction, especially when it occurs in the presence of additional stressors such as oxidative or nitrosative stress [64]. Ca²⁺ signaling has emerged as a critical modulator of mitochondrial function, with evidence indicating that Ca²⁺ contributes to the initiation of mitochondrion-dependent apoptosis [65]. Mitochondria serve as both ATP producers and crucial intracellular Ca²⁺ buffers. The mCUP, located on the inner mitochondrial membrane, plays a pivotal role in mediating Ca²⁺ influx into the mitochondrial matrix. Under normal physiological conditions, even modest fluctuations in Ca²⁺ levels are sufficient to activate dehydrogenases like FoF1-ATP, promoting ATP synthesis. However, under pathophysiological conditions, these processes are disrupted. Inositol trisphosphate receptors (IP₃Rs) are essential for maintaining intracellular calcium homeostasis. The release of Ca²⁺ from IP₃Rs functions as a second messenger, orchestrating various intracellular processes and inter-organellar communication in both physiological and pathological contexts. Over activation of IP₃Rs has been linked to the pathogenesis of several cardiac disorders, including ischemia, diabetes-induced arrhythmias, and cardiac hypertrophy. Dysregulated Ca²⁺ signaling within cytosolic, mitochondrial, and nucleoplasmic compartments contributes to the progression of these diseases [66]. Interestingly, an adaptive mechanism through which mitochondria mitigate ROS-induced damage is apoptosis induction. This process involves an increase in mitochondrial outer membrane permeability, leading to solute and water influx into the matrix, loss of membrane potential, cessation of ATP synthesis, and excessive mitochondrial calcium uptake—culminating in complete mitochondrial failure [67].

4. Mitochondrial Metabolic Alterations and Mitochondrial Dynamics

It is well established that mitochondrial dysfunction is a hallmark of cardiovascular diseases (CVDs), manifesting as impaired oxidative phosphorylation, excessive ROS production, altered calcium signaling, and disrupted metabolic homeostasis. Conditions such as ischemia-reperfusion injury, hypertension and diabetic cardiomyopathy are associated with compromised mitochondrial energetics and structural integrity, culminating in cardiac contractile dysfunction [68,69,70,71,72,73,74]. The heart is an energetically demanding organ, necessitating a continuous and substantial supply of adenosine triphosphate (ATP) to sustain contractile function. Despite its limited ATP reserves, the heart maintains an exceptionally efficient bioenergetic system, predominantly driven by mitochondria, which constitute nearly 30% of cardiomyocyte volume. These organelles facilitate ATP generation through oxidative phosphorylation, orchestrating substrate oxidation, electron transport, and ATP synthesis to meet the heart’s metabolic demands [75,76,77,78,79]. Mitochondrial function is intricately linked to substrate availability, with ATP synthesis reliant on the oxidation of fatty acids, glucose, ketone bodies, and amino acids. It should be mentioned that biologically active amines such as spermine and agmatine have distinct roles in mitochondrial function that differentiate them from other amines; notably, spermine undergoes oxidative deamination by amine oxidases, producing ROS, which may further exacerbate the opening of the MPTP and contribute to apoptosis [44].

In the healthy myocardium, fatty acid oxidation contributes approximately 60–70% of ATP production, while glucose metabolism accounts for 20–30% [80,81,82,83]. The efficiency of ATP synthesis per unit of oxygen is higher for glucose than for fatty acids, a critical factor under hypoxic or ischemic conditions [84,85,86,87]. The intrinsic compensatory mechanisms that regulate intracellular calcium and the antioxidant defense system, which typically maintain mitochondrial substrate oxidation and ATP generation, become insufficient in the context of chronic cardiac dysfunction [88,89,90]. It should be mentioned that insulin resistance in diabetes reduces glucose transporter expression and pyruvate dehydrogenase activity, shifting myocardial energy reliance towards fatty acid β-oxidation. This metabolic shift increases oxygen consumption while decreasing ATP yield efficiency, predisposing mitochondria to oxidative stress and lipotoxic damage [91,92,93,94]. Prolonged metabolic perturbations, including excessive fatty acid uptake and β-oxidation inefficiencies, promote lipid accumulation, mitochondrial dysfunction, and cardiomyocyte apoptosis. These maladaptive changes contribute to myocardial energy deficits, compromised contractility, and heightened susceptibility to heart failure [95,96,97,98,99,100]. In addition, the chronic dysregulation of glycolipid metabolism in diabetes leads to both excessive ROS production and impaired ROS clearance. Mitochondria serve as the primary source of ROS in diabetic cardiomyocytes, and their dysfunction perpetuates a vicious cycle of oxidative damage. This process severely compromises cardiomyocyte function and survival by exacerbating metabolic disturbances, energy depletion, and oxidative stress-driven apoptosis [101]. However, it should be noted that chronic hyperglycemia during diabetes, further increases mitochondrial ROS production and impairs endogenous antioxidant defense mechanisms thus leading to excessive apoptosis and myocardial dysfunction [102,103]. A schematic diagram indicating the role of oxidative stress in inducing mitochondrial metabolic changes associated with depression in energy stores, cellular death and lipid deposits in cardiomyocytes and subsequent cardiac dysfunction in diseased hearts is shoen in Figure 6.

It should be pointed out that mitochondrial generated oxidative stress, signal transduction, metabolic reprogramming, regulation of iron and cell death depend on the mitochondrial quality control (MQC) system that includes mitochondrial dynamics (fission and fusion cycles) and mitochondrial biogenesis to maintain structural integrity and cardiac function [104,105,106]. Thus, targeting mitochondrial bioenergetics and metabolic flexibility represents a promising therapeutic strategy for mitigating CVD progression and preserving cardiac function. The mitochondrial ribosomal protein S5 (MRPS5/uS5m) is essential for maintaining mitochondrial protein translation and oxidative phosphorylation. Loss of MRPS5 in the developing heart leads to embryonic lethality, while postnatal loss impairs oxidative phosphorylation and mitochondrial protein synthesis, contributing to cardiac hypertrophy and heart failure [107]. Mitochondrial dynamics, including fusion and fission processes, are integral to maintaining mitochondrial function and integrity [108]. Fusion proteins such as Mfn-1, Mfn-2, and OPA-1 are essential for mitochondrial stability, as their inhibition leads to dilated cardiomyopathy, contractile dysfunction, increased apoptosis, and mitochondrial fragmentation [109]. Deletion of these fusion proteins results in abnormal mitochondrial morphology, ventricular wall thickening, and eccentric hypertrophy. Conversely, excessive mitochondrial fission disrupts mitochondrial mass, impairs oxidative phosphorylation, and results in ATP deficits, mitochondrial permeabilization, cytochrome C release, and apoptosis. The absence of dynamin-related protein 1 (Drp1), a key fission protein, results in lethal dilated cardiomyopathy [110], further highlighting the critical balance between fusion and fission in maintaining cardiac mitochondrial function.

Alterations in mitochondrial ultrastructure and bioenergetics are widely observed in heart failure patients, particularly in the later disease stages. These changes include reductions in the activities of respiratory chain complexes (I–IV) and impaired oxidative phosphorylation capacity. Interestingly, in cases of chronic hypertrophy without systolic dysfunction, mitochondrial function appears to be preserved or even enhanced in both animal models and human studies [111,112,113,114,115,116,117,118,119,120,121,122]. Initial stages of cardiac hypertrophy are often characterized by an increase in oxidative phosphorylation activity, which gradually declines as the disease progresses toward heart failure [16,123]. A reduction in the expression of key oxidative phosphorylation components has been linked to mitochondrial respiratory deficits in heart failure and cardiomyopathies [124,125]. It is pointed out that in ventricular fibrillation, mitochondrial damage activates the mitochondrial apoptotic pathway, characterized by the release of cytochrome C into the cytosol, a reduction in caspase-9 levels, and the subsequent activation of caspase-3. This cascade coincides with significant impairments in LV function. Notably, cytochrome C "leaks" into the bloodstream, and its concentration is inversely proportional to survival outcomes [126]. Taken together, these findings underline the critical role of mitochondria during cardiac resuscitation by modulating both energy metabolism and apoptotic signaling pathways, positioning mitochondrial-targeted therapies as promising strategies for enhancing outcomes during cardiac resuscitation [126].

5. Novel Interventions Targeting Mitochondria in Different Cardiac Pathologies

In view of the fact that mitochondria constitute 30-40% of the cardiomyocyte [127], and that mitochondria are considered as the key determinants of cardiac injury and dysfunction [128,129,130,131,132], mitochondria represent a viable target for therapeutic intervention. For example, the regulation of mitochondrial Ca²⁺- uptake and the interplay between various molecules and pathways offer promising avenues for therapeutic intervention. Mitochondria have been suggested to exhibit a cardioprotective role due to the presence of KATP channels [133]. In this regard, cardioprotection via hypoxic preconditioning or exposure to the ATP-dependent K⁺- channel opener diazoxide increases mitochondrial resistance to oxidative damage. Thus, targeting the MPTP, either by direct inhibition or modulation of mitochondrial stressors, represents a promising therapeutic approach for conditions such as I/R-injury [65,134]. Interestingly, the reperfusion injury salvage kinase (RISK) pathway for cardioprotection involves the prevention of the opening of the membrane permeability transition pore and subsequent attenuation of cell death [135]. Thus, this pathway has emerged as an important cardioprotective target in I/R-injury.

In reperfusion-induced injury is a significant challenge during cardiac surgery, coronary thrombosis treatment, and stroke management. Preventing MPTP opening, either directly with agents like cyclosporine A or indirectly by reducing oxidative stress or Ca²⁺- overload, represents a potential therapeutic strategy to mitigate reperfusion injury. Additionally, mice deficient in Cyclophilin D (CyP-D), a critical component of the MPTP, are protected from ischemia/reperfusion injury in the heart, further substantiating the role of MPTP in mediating cellular injury [136]. In less severe cellular insults, the MPTP may open transiently, leading to mitochondrial swelling sufficient to trigger cytochrome C release and activation of the apoptotic pathway, rather than necrosis. However, CyP-D knockout mice do not exhibit enhanced protection against a broad range of apoptotic stimuli, suggesting that the MPTP is not universally involved in apoptosis [136]. Recently, it has been suggested that circadian rhythm may play an important role in the control of I/R-injury [137]. MiRNAs regulate mitochondrial apoptosis through an effect on mitochondrial fission and fusion, generation of ROS and dysregulating Ca²⁺-homeostasis [138]. Interestingly, it has been suggested that mitochondrial transplantation has the potential to exert beneficial actions in I/R-injury; however, clinical application is limited [139]. On the other hand, mitochondrial regeneration can be seen to increase oxidative phosphorylation and decrease oxidative stress and thus may be of clinical value under conditions of ischemic insult of the heart [140]. In fact, targeting MQC has emerged as a promising target in mitigating hypoxia-related cardiac dysfunction [141].

In the context of diabetic cardiomyopathy, the role of mCUP and its regulatory subunit, mitochondrial calcium uptake protein 1 (MICU1), has emerged as a critical factor in Ca²⁺- transport. Studies have shown that in diabetic mice, there is an upregulation of MICU1 expression in the heart, accompanied by a downregulation of MCU and associated regulatory proteins, such as EMRE, a key mCUP subunit. This imbalance leads to compromised mitochondrial Ca²⁺- uptake, diminished mitochondrial function, and, consequently, reduced cardiac performance. Importantly, restoring MCU expression has been shown to ameliorate both mitochondrial and cardiac dysfunction, highlighting the therapeutic potential of restoring mitochondrial Ca²⁺ homeostasis in diabetic cardiomyopathy treatment [142,143]. Distinct isoforms of IP₃Rs, IP₃R1 and IP₃R2, exhibit different roles in cardiac pathology. IP₃R1 is particularly involved in cardiac ischemia and arrhythmias associated with diabetes, while IP₃R2 is implicated in sepsis-induced cardiomyopathy and hypertrophy [66]. Thus, IP₃Rs have been shown to play pivotal roles in various forms of cell death, such as apoptosis, pyroptosis, and ferroptosis, underlining their multifaceted involvement in cardiac disease. Targeting IP₃Rs, either through genetic manipulation or pharmacological inhibition using IP₃R antagonists, has emerged as a promising therapeutic strategy to mitigate IP₃R-related pathologies, offering potential for therapeutic intervention in CVD [66].

6. Conclusion

From the foregoing discussion, it is evident that mitochondria are not only involved in energy production, but are also the major source of oxidative stress production as well as intracellular Ca²⁺- accumulation. In fact, the development of oxidative stress and the occurrence of mitochondrial Ca²⁺- overload are the main mechanisms for induction of energy store depletion and cardiac dysfunction. It is noteworthy that ROS generated by the activation of sarcolemmal NADPH oxidase 2 as well as extra-mitochondrial (endothelial cells, serum, cytosol) xanthine oxidase are also considered to promote the generation of mitochondrial oxidative stress during the development of heart disease [7,8,144,145,146,147]. It should be mentioned that mitochondria are known to contain different components for the production of ROS such as the electron transport chain, NADPH oxidase 4 and monoamine oxidase, in addition to endogenous antioxidants such as SOD, CAT and glutathione peroxidase. Particularly, it may also be noted that there occurs accumulation of different vasoactive hormones such as angiotensin II and endothelin (activators of NADPH oxidase 4) as well as catecholamines and serotonin (substrates for oxidation by MAO) in cardiomyocytes of diseased hearts. Furthermore, the occurrence of mitochondrial Ca²⁺- overload has been associated with the activation of MAO and the induction of defects in electron transport system in mitochondria in ischemic heart disease.

There is now a wealth of information that has demonstrated that mitochondrial Ca²⁺- overload and increased generation of ROS are central features in cardiac dysfunction in different cardiac pathologies including heart failure, diabetic cardiomyopathy and ischemia-reperfusion injury. Although mitochondria accumulate high amounts of Ca²⁺ and thus serve as an intracellular Ca²⁺ reservoir, abnormalities in the processes involved in energy production through oxidative phosphorylation produce an oxidative stress that impacts the structural and functional integrity of the cell. Indeed, ROS-induced ROS production by mitochondria exacerbates ROS generation and severity of oxidative stress. The mitochondria-generated ROS as a consequence of mitochondrial Ca²⁺-overload leads to further deterioration of mitochondrial function. Accordingly, the mitochondria present viable therapeutic target for the prevention of cardiac dysfunction in at-risk population. Therefore, the development of specific interventions that are effective in attenuating mitochondrial metabolic alterations as well as the development of novel antioxidants that target mitochondrial ROS generating systems could be highly beneficial.