Exercise and Doxorubicin Modify Markers of Iron Overload and Cardiolipin Deficiency in Cardiac Mitochondria

Abstract

Doxorubicin (DOX) is a chemotherapeutic agent highly effective at limiting cancer progression. Despite the efficacy of this anticancer drug, the clinical use of DOX is limited due to cardiotoxicity. The cardiac mitochondria are implicated as the primary target of DOX, resulting in inactivation of electron transport system complexes, oxidative stress, and iron overload. However, it is established that the cardiac mitochondrial subpopulations reveal differential responses to DOX exposure, with subsarcolemmal (SS) mitochondria demonstrating redox imbalance and the intermyofibrillar (IMF) mitochondria showing reduced respiration. In this regard, exercise training is an effective intervention to prevent DOX-induced cardiac dysfunction. Although it is clear that exercise confers mitochondrial protection, it is currently unknown if exercise training mitigates DOX cardiac mitochondrial toxicity by promoting beneficial adaptations to both the SS and IMF mitochondria. To test this, SS and IMF mitochondria were isolated from sedentary and exercise-preconditioned female Sprague Dawley rats exposed to acute DOX treatment. Our findings reveal a greater effect of exercise preconditioning on redox balance and iron handling in the SS mitochondria of DOX-treated rats compared to IMF, with rescue of cardiolipin synthase 1 expression in both subpopulations. These results demonstrate that exercise preconditioning improves mitochondrial homeostasis when combined with DOX treatment, and that the SS mitochondria display greater protection compared to the IMF mitochondria. These data provide important insights into the molecular mechanisms that are in part responsible for exercise-induced protection against DOX toxicity.

Targeting mitochondrial dynamics proteins for the treatment of doxorubicin-induced cardiotoxicity

“…Due to the high affinity between DOX and cardiolipin in cardiomyocytes, DOX is more likely to accumulate in mitochondria than in cytoplasm, and studies have shown that DOX has a greater affinity for subsarcolemmal mitochondria compared to intermyofibrillar mitochondria, which difference occurs potentially as a result of greater concentrations of cardiolipin within this mitochondrial fraction (Kavazis et al, 2017). And exercise preconditioning greatly improves subsarcolemmal mitochondria homeostasis by acting on redox balance and iron handling in subsarcolemmal mitochondria upon acute DOX treatment (Montalvo et al, 2023). According to Morton, by boosting the expression of mitochondria-specific ATP-binding cassette (ABC) transporters and lowering the accumulation of mitochondrial DOX, 2 weeks of exercise preconditioning is sufficient to prevent cardiorespiratory failure (Morton et al, 2019).…”

The IRONy in Athletic Performance

“…Besides maintaining cellular energy, studies extensively highlight the role of mitochondria in skeletal muscle atrophy [49]. Further, perturbation in iron homeostasis causes an overall decline in mitochondrial function as evidenced by diminished mitochondrial Ca 2+ handling capacity, increase in mitochondrial oxidative damage, reduced succinate dehydrogenase and cytochrome-c levels, and impaired myoglobin activity in the muscles [36,[50][51][52][53].…”