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

Abstract

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.

Mitochondrial Effects of Common Cardiovascular Medications: The Good, the Bad and the Mixed

“…In this review, we attempted to emphasize the complexity of mitochondrial effects of the therapeutic armamentarium currently used in cardiovascular diseases as promising prospects for future translational research into safety pharmacology and drug development. The need for the assessment of mitochondrial toxicity by means of modern testing platforms should be included in preclinical safety pharmacology in order to prevent drug attrition during development, and also decrease the risk of side-/off target deleterious effects, has been recently emphasized by a comprehensive review [ 325 ]. While the concept of ”clinical trial in a dish” for drug development is strongly supported by the pharmaceutical industry [ 326 ], it has to be mentioned that it will never be able to appropriately recapitulate the complexity of the clinical situation where both disease and ageing-related neurohormonal activation/impaired signaling occur.…”

Mitochondria: It is all about energy

“…Oncological drugs are reported to cause structural damage to mitochondria, including downregulated ferroptosis, accumulation of lipid peroxides, mitochondrial swelling, cristae disappearance, and matrix cavitation, as found in research with the oncological medicine doxorubicin (DOX) (Tadokoro et al, 2020;Tang et al, 2022). Related to mitochondrial complexes, zoniporide, naproxen, dronedarone, and mubritinib inhibit complex I (Tang et al, 2022). Complex II is compromised by propranolol and atenolol.…”

“…Modern life puts a real burden on the normal functioning of mitochondria in multiple organs. Factors such as sitting time ( Nogueira Silva Lima et al, 2021 ), high-calorie diet ( Nogueira Silva Lima et al, 2021 ), sleep disturbance ( Saner et al, 2021 ), and alcohol abuse ( Wang et al, 2010 ) and factors that are hardly evitable such as environmental pollution ( Grytting et al, 2022 ), light pollution ( Grytting et al, 2022 ) diesel exhaust and the use of multiple medicines, including NAISDs ( Tang et al, 2022 ), can produce a state of low-grade inflammation (LGI) associated with many chronic diseases ( de Punder and Pruimboom, 2015a ). LGI and mitochondrial dysfunction are two cross-connected mechanisms.…”

The Emerging Role of Autophagy as a Target of Environmental Pollutants: An Update on Mechanisms

“…BCL2 interacting protein 3 (BNIP3) is essential for arsenic trioxide (As 2 O 3 )-induced autophagy in malignant glioma cells [ 84 ]. As 2 O 3 -induced autophagic cell death involves LC3 and mitochondrial membrane rupture but not caspase activation [ 85 ]. As 2 O 3 is a powerful autophagy inducer that appears to need MAPK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway activation but not MAPK8/JNK or AKT/mTOR [ 86 ].…”