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Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.

ABSTRACT: Heart failure is a serious global health challenge, affecting more than 6.2 million people in the United States and is projected to reach over 8 million by 2030. Independent of etiology, failing hearts share common features, including defective calcium (Ca²⁺) handling, mitochondrial Ca²⁺ overload, and oxidative stress. In cardiomyocytes, Ca²⁺ not only regulates excitation-contraction coupling, but also mitochondrial metabolism and oxidative stress signaling, thereby controlling the function and actual destiny of the cell. Understanding the mechanisms of mitochondrial Ca²⁺ uptake and the molecular pathways involved in the regulation of increased mitochondrial Ca²⁺ influx is an ongoing challenge in order to identify novel therapeutic targets to alleviate the burden of heart failure. In this review, we discuss the mechanisms underlying altered mitochondrial Ca²⁺ handling in heart failure and the potential therapeutic strategies.

SUBMITTER: Dridi H

PROVIDER: S-EPMC10527470 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.

Dridi Haikel H Santulli Gaetano G Bahlouli Laith L Miotto Marco C MC Weninger Gunnar G Marks Andrew R AR

Biomolecules 20230919 9

Heart failure is a serious global health challenge, affecting more than 6.2 million people in the United States and is projected to reach over 8 million by 2030. Independent of etiology, failing hearts share common features, including defective calcium (Ca2+) handling, mitochondrial Ca2+ overload, and oxidative stress. In cardiomyocytes, Ca2+ not only regulates excitation-contraction coupling, but also mitochondrial metabolism and oxidative stress signaling, ther ...[more]

PMID: 37759809

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Project description:Iron (Fe) plays an essential role in many physiological processes. Hereditary hemochromatosis or frequent blood transfusions often cause iron overload (IO), which can lead to cardiomyopathy and arrhythmias; however, the underlying mechanism is not well defined. In the present study, we assess the hypothesis that IO promotes arrhythmias via reactive oxygen species (ROS) production, mitochondrial membrane potential (??m) depolarization, and disruption of cytosolic Ca dynamics. In ventricular myocytes isolated from wild type (WT) mice, both cytosolic and mitochondrial Fe levels were elevated following perfusion with the Fe3+/8-hydroxyquinoline (8-HQ) complex. IO promoted mitochondrial superoxide generation (measured using MitoSOX Red) and induced the depolarization of the ??m (measured using tetramethylrhodamine methyl ester, TMRM) in a dose-dependent manner. IO significantly increased the rate of Ca wave (CaW) formation measured in isolated ventricular myocytes using Fluo-4. Furthermore, in ex-vivo Langendorff-perfused hearts, IO increased arrhythmia scores as evaluated by ECG recordings under programmed S1-S2 stimulation protocols. We also carried out similar experiments in cyclophilin D knockout (CypD KO) mice in which the mitochondrial permeability transition pore (mPTP) opening is impaired. While comparable cytosolic and mitochondrial Fe load, mitochondrial ROS production, and depolarization of the ??m were observed in ventricular myocytes isolated from both WT and CypD KO mice, the rate of CaW formation in isolated cells and the arrhythmia scores in ex-vivo hearts were significantly lower in CypD KO mice compared to those observed in WT mice under conditions of IO. The mPTP inhibitor cyclosporine A (CsA, 1 µM) also exhibited a protective effect. In conclusion, our results suggest that IO induces mitochondrial ROS generation and ??m depolarization, thus opening the mPTP, thereby promoting CaWs and cardiac arrhythmias. Conversely, the inhibition of mPTP ameliorates the proarrhythmic effects of IO.

Project description:In neuroinflammatory and neurodegenerative disorders such as multiple sclerosis, mitochondrial damage caused by oxidative stress is believed to contribute to neuroaxonal damage. Previously, we demonstrated that exposure to hydrogen peroxide (H2O2) alters mitochondrial morphology and motility in myelinated axons and that these changes initiate at the nodes of Ranvier, where numerous sodium channels are located. Therefore, we suggested that mitochondrial damage may lead to ATP deficit, thereby affecting the efficiency of the sodium-potassium ATPase and eventually leading to sodium overload in axons. The increased intra-axonal sodium may revert the axonal sodium-calcium exchangers and thus may lead to a pathological calcium overload in the axoplasm and mitochondria. Here, we used the explanted murine ventral spinal roots to investigate whether modulation of sodium or calcium influx may prevent mitochondrial alterations in myelinated axons during exogenous application of H2O2 inducing oxidative stress. For that, tetrodotoxin, an inhibitor of voltage-gated sodium ion channels, and ruthenium 360, an inhibitor of the mitochondrial calcium uniporter, were applied simultaneously with hydrogen peroxide to axons. Mitochondrial shape and motility were analyzed. We showed that inhibition of axonal sodium influx prevented oxidative stress-induced morphological changes (i.e., increase in circularity and area and decrease in length) and preserved mitochondrial membrane potential, which is crucial for ATP production. Blocking mitochondrial calcium uptake prevented decrease in mitochondrial motility and also preserved membrane potential. Our findings indicate that alterations of both mitochondrial morphology and motility in the contexts of oxidative stress can be counterbalanced by modulating intramitochondrial ion concentrations pharmacologically. Moreover, motile mitochondria show preserved membrane potentials, pointing to a close association between mitochondrial motility and functionality.

Project description:BACKGROUND:Phosphodiesterase type 5 (PDE5) inhibition has been shown to exert profound beneficial effects in the failing heart, suggesting a significant role for PDE5 in the development of congestive heart failure (CHF). The purpose of this study is to test the hypothesis that oxidative stress causes increased PDE5 expression in cardiac myocytes and that increased PDE5 contributes to the development of CHF. METHODS AND RESULTS:Myocardial PDE5 expression and cellular distribution were determined in left ventricular samples from patients with end-stage CHF and normal donors and from mice after transverse aortic constriction (TAC)-induced CHF. Compared with donor human hearts, myocardial PDE5 protein was increased approximately equal 4.5-fold in CHF samples, and the increase of myocardial PDE5 expression was significantly correlated with myocardial oxidative stress markers 3'-nitrotyrosine or 4-hydroxynonenal expression (P<0.05). Histological examination demonstrated that PDE5 was mainly expressed in vascular smooth muscle in normal donor hearts, but its expression was increased in both cardiac myocytes and vascular smooth muscle of CHF hearts. Myocardial PDE5 protein content and activity also increased in mice after TAC-induced CHF (P<0.05). When the superoxide dismutase (SOD) mimetic M40401 was administered to attenuate oxidative stress, the increased PDE5 protein and activity caused by TAC was blunted, and the hearts were protected against left ventricular hypertrophy and CHF. Conversely, increased myocardial oxidative stress in superoxide dismutase 3 knockout mice caused a greater increase of PDE5 expression and CHF after TAC. In addition, administration of sildenafil to inhibit PDE5 attenuated TAC-induced myocardial oxidative stress, PDE5 expression, and CHF. CONCLUSIONS:Myocardial oxidative stress increases PDE5 expression in the failing heart. Reducing oxidative stress by treatment with M40401 attenuated cardiomyocyte PDE5 expression. This and selective inhibition of PDE5 protected the heart against pressure overload-induced left ventricular hypertrophy and CHF.

Project description:Oxidative stress has been shown to induce cell death in a wide range of human diseases including cardiac ischemia/reperfusion injury, drug induced cardiotoxicity, and heart failure. However, the mechanism of cell death induced by oxidative stress remains incompletely understood. Here we provide new evidence that oxidative stress primarily induces ferroptosis, but not apoptosis, necroptosis, or mitochondria-mediated necrosis, in cardiomyocytes. Intriguingly, oxidative stress induced by organic oxidants such as tert-butyl hydroperoxide (tBHP) and cumene hydroperoxide (CHP), but not hydrogen peroxide (H2O2), promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to increased lipid peroxidation. Moreover, elevated oxidative stress is also linked to labile iron overload through downregulation of the transcription suppressor BTB and CNC homology 1 (Bach1), upregulation of heme oxygenase 1 (HO-1) expression, and enhanced iron release via heme degradation. Strikingly, oxidative stress also promoted HO-1 translocation to mitochondria, leading to mitochondrial iron overload and lipid reactive oxygen species (ROS) accumulation. Targeted inhibition of mitochondrial iron overload or ROS accumulation, by overexpressing mitochondrial ferritin (FTMT) or mitochondrial catalase (mCAT), respectively, markedly inhibited oxidative stress-induced ferroptosis. The levels of mitochondrial iron and lipid peroxides were also markedly increased in cardiomyocytes subjected to simulated ischemia and reperfusion (sI/R) or the chemotherapeutic agent doxorubicin (DOX). Overexpressing FTMT or mCAT effectively prevented cardiomyocyte death induced by sI/R or DOX. Taken together, oxidative stress induced by organic oxidants but not H2O2 primarily triggers ferroptotic cell death in cardiomyocyte through GPX4 and Bach1/HO-1 dependent mechanisms. Our results also reveal mitochondrial iron overload via HO-1 mitochondrial translocation as a key mechanism as well as a potential molecular target for oxidative stress-induced ferroptosis in cardiomyocytes.

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Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.

Publications

Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.

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