Structural and Functional Remodeling of Mitochondria in Cardiac Diseases

Sun, Xiaonan; Alford, Jalen; Qiu, Hongyu

doi:10.3390/ijms22084167

Cited by 20 publications

(15 citation statements)

References 140 publications

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“…Causes for mitochondrial dysfunction are manifold and include modifications of proteins in the electron transport chain, changes in calcium-homeostasis, production of reactive oxygen species, which is often also a consequence of mitochondrial dysfunction, or defects in mitochondrial structure and dynamics (Sun et al 2021 ; Zhou and Tian 2018 ). We used the seahorse technology to characterize the mitochondrial function.…”

Section: Resultsmentioning

confidence: 99%

The potential of remdesivir to affect function, metabolism and proliferation of cardiac and kidney cells in vitro

et al. 2022

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Remdesivir is a prodrug of a nucleoside analog and the first antiviral therapeutic approved for coronavirus disease. Recent cardiac safety concerns and reports on remdesivir-related acute kidney injury call for a better characterization of remdesivir toxicity and understanding of the underlying mechanisms. Here, we performed an in vitro toxicity assessment of remdesivir around clinically relevant concentrations (Cmax 9 µM) using H9c2 rat cardiomyoblasts, neonatal mouse cardiomyocytes (NMCM), rat NRK-52E and human RPTEC/TERT1 cells as cell models for the assessment of cardiotoxicity or nephrotoxicity, respectively. Due to the known potential of nucleoside analogs for the induction of mitochondrial toxicity, we assessed mitochondrial function in response to remdesivir treatment, early proteomic changes in NMCM and RPTEC/TERT1 cells and the contractile function of NMCM. Short-term treatments (24 h) of H9c2 and NRK-52E cells with remdesivir adversely affected cell viability by inhibition of proliferation as determined by significantly decreased 3H-thymidine uptake. Mitochondrial toxicity of remdesivir (1.6–3.1 µM) in cardiac cells was evident by a significant decrease in oxygen consumption, a collapse of mitochondrial membrane potential and an increase in lactate secretion after a 24–48-h treatment. This was supported by early proteomic changes of respiratory chain proteins and intermediate filaments that are typically involved in mitochondrial reorganization. Functionally, an impedance-based analysis showed that remdesivir (6.25 µM) affected the beat rate and contractility of NMCM. In conclusion, we identified adverse effects of remdesivir in cardiac and kidney cells at clinically relevant concentrations, suggesting a careful evaluation of therapeutic use in patients at risk for cardiovascular or kidney disease.

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Section: Resultsmentioning

confidence: 99%

The potential of remdesivir to affect function, metabolism and proliferation of cardiac and kidney cells in vitro

et al. 2022

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“…Defective autophagy and mitophagy may lead to accumulation of intracellular damage and finally malfunction of the mitochondria. Damaged mitochondria, which are shorter in length than normal ones, have a worse respiratory ability and fail to produce enough ATP for cell function ( Sun et al, 2021 ). So, we tested the influence of H 2 O 2 treatment on autophagy flux, mitophagy, and function of the mitochondria.…”

Section: Resultsmentioning

confidence: 99%

Vanillic acid attenuates H2O2-induced injury in H9c2 cells by regulating mitophagy via the PINK1/Parkin/Mfn2 signaling pathway

Mei

Sun²,

Xu³

et al. 2022

Front. Pharmacol.

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Vanillic acid, a phenolic compound mainly obtained from the foot of Picrorhiza scrophulariiflora Pennell, has been demonstrated to possess a cardiovascular-protective effect in previous studies. However, there is lack of research on vanillic acid protecting cardiomyocytes from oxidative stress injury by mediating mitophagy. In the present study, oxidative stress injury in the H9c2 cell line was induced by H2O2. Our results confirmed that vanillic acid mitigated apoptosis and injury triggered by oxidative stress, evidenced by the decline in production of reactive oxygen species and malondialdehyde and level of lactate dehydrogenase and the increase of superoxide dismutase and glutathione. The use of vanillic acid could also improve the polarization of mitochondrial membrane potential and decrease the cellular calcium level. After treatment by vanillic acid, impaired autophagy flux and mitophagy were improved, and the length of mitochondria was restored. Vanillic acid increased the expression of PINK1, Parkin, Mfn2, and the ratio of LC3-II/LC3-I and decreased the expression of p62. But, under the intervention of mitophagy inhibitor 3-MA, vanillic acid could not change the expression of PINK1/Parkin/Mfn2 and downstream genes to affect cell autophagy, mitophagy, and mitochondrial function. Our findings suggested that vanillic acid activated mitophagy to improve mitochondrial function, in which the PINK1/Parkin/Mfn2 pathway could be the potential regulatory mechanism.

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“…The heart consumes about 6 kg of ATP per day, which is mainly generated through mitochondrial OXPHOS from the catabolism of lipids and carbohydrates [ 133 , 134 , 135 ]. Glucose, lactate, and fatty acids are oxidized in the mitochondrion and produce a common end product (i.e., acetyl-CoA), which then goes through eight enzymatic steps of the Krebs cycle, where electrons are extracted from TCA intermediates in the form of reducing equivalents (nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH 2 )) ( Figure 2 A).…”

Section: Main Properties Of Mitochondria and Drug-induced Mitochondri...mentioning

confidence: 99%

“…Oxidative stress is induced in response to a decreased level of antioxidant enzymes and increased production of ROS. Mitochondria, while being a primary source of ROS themselves, also suffer from ROS-mediated damages caused by peroxidation of macromolecules including proteins, lipids, and DNA [ 135 , 195 , 196 , 197 ]. Therefore, the balance between mtROS production and elimination is critical for mitochondria.…”

Section: Main Properties Of Mitochondria and Drug-induced Mitochondri...mentioning

confidence: 99%

Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation

Tang

Wang

et al. 2022

Pharmaceutics

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Drug-induced cardiotoxicity not only leads to the attrition of drugs during development, but also contributes to the high morbidity and mortality rates of cardiovascular diseases. Comprehensive testing for proarrhythmic risks of drugs has been applied in preclinical cardiac safety assessment for over 15 years. However, other mechanisms of cardiac toxicity have not received such attention. Of them, mitochondrial impairment is a common form of cardiotoxicity and is known to account for over half of cardiovascular adverse-event-related black box warnings imposed by the U.S. Food and Drug Administration. Although it has been studied in great depth, mitochondrial toxicity assessment has not yet been incorporated into routine safety tests for cardiotoxicity at the preclinical stage. This review discusses the main characteristics of mitochondria in cardiomyocytes, drug-induced mitochondrial toxicities, and high-throughput screening strategies for cardiomyocytes, as well as their proposed integration into preclinical safety pharmacology. We emphasize the advantages of using adult human primary cardiomyocytes for the evaluation of mitochondrial morphology and function, and the need for a novel cardiac safety testing platform integrating mitochondrial toxicity and proarrhythmic risk assessments in cardiac safety evaluation.

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Structural and Functional Remodeling of Mitochondria in Cardiac Diseases

Cited by 20 publications

References 140 publications

The potential of remdesivir to affect function, metabolism and proliferation of cardiac and kidney cells in vitro

The potential of remdesivir to affect function, metabolism and proliferation of cardiac and kidney cells in vitro

Vanillic acid attenuates H2O2-induced injury in H9c2 cells by regulating mitophagy via the PINK1/Parkin/Mfn2 signaling pathway

Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation

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