Radiation-induced disruption of cardiac mitochondrial bioenergetics and nucleotide homeostasis in mice

Aims

Cardiac stereotactic body radiotherapy (SBRT) has emerged as a promising non-invasive treatment for refractory ventricular tachycardia (VT). Intriguingly, the clinical benefit of SBRT often occurs within days of treatment, preceding the development of radiation-induced fibrosis, suggesting alternative underlying mechanisms. This study aimed to investigate the acute and persistent effects of ionizing radiation on cardiac bioenergetics and mitochondrial function, providing mechanistic insights into early cardiac responses to radiation exposure.

Methods and results

We employed a translational multi-model approach, including HL-1 mouse cardiomyocytes and ex vivo mouse left ventricular living myocardial slices (LMS). Bioenergetic profiling, assessment of mitochondrial respiration and calcium handling were performed following exposure to clinically relevant radiation doses (10 Gy and 25 Gy). In HL-1 cardiomyocytes, 10 Gy induced acute bioenergetic stress, characterized by reduced adenylate energy charge, cytoskeletal disorganization, and impaired mitochondrial respiration, accompanied by increased calcium oscillation amplitude. 25 Gy exposure led to NAD ⁺ depletion but paradoxically enhanced mitochondrial respiratory capacity, suggesting an adaptive metabolic response. Murine myocardial slices demonstrated reduced creatine content while preserving energy balance as indicated by phosphocreatine/ATP ratio, indicating tissue-level metabolic resilience. These findings reveal model-specific metabolic perturbations induced by cardiac irradiation, underscoring the importance of tissue complexity in modulating the cardiac response to radiation.

Conclusion

This study demonstrates that ionizing radiation at 10 Gy and 25 Gy induced dose- and model-dependent bioenergetic alterations in cardiac cells and tissues, including changes in mitochondrial respiration, nucleotide levels, and redox balance. While 10 Gy exacerbated metabolic disruption, 25 Gy triggered partial recovery, highlighting differential responses across cellular and tissue levels. These metabolic changes may contribute to the immediate effects of cardiac SBRT and potentially to long-term cardiotoxicity.

Translational Perspective

Our study provides novel mechanistic insights into the metabolic effects of cardiac irradiation, revealing acute mitochondrial stress, redox imbalance and alterations in calcium homeostasis in cardiomyocytes. These early bioenergetic changes may contribute to both the immediate anti-arrhythmic effects and the potential long-term cardiotoxicity of stereotactic body radiation therapy. Understanding these molecular responses is essential to optimize the therapeutic window of cardiac radioablation and minimize adverse effects.

GRAPHICAL ABSTRACT