Emerging mitochondrial signaling mechanisms in cardio-oncology: beyond oxidative stress

Many anticancer therapies (CTx) have cardiotoxic side effects that limit their therapeutic potential and cause long-term cardiovascular complications in cancer survivors. This has given rise to the field of cardio-oncology, which recognizes the need for basic, translational, and clinical research focused on understanding the complex signaling events that drive CTx-induced cardiovascular toxicity. Several CTx agents cause mitochondrial damage in the form of mitochondrial DNA deletions, mutations, and suppression of respiratory function and ATP production. In this review, we provide a brief overview of the cardiovascular complications of clinically used CTx agents and discuss current knowledge of local and systemic secondary signaling events that arise in response to mitochondrial stress/damage. Mitochondrial oxidative stress has long been recognized as a contributor to CTx-induced cardiotoxicity; thus, we focus on emerging roles for mitochondria in epigenetic regulation, innate immunity, and signaling via noncoding RNAs and mitochondrial hormones. Because data exploring mitochondrial secondary signaling in the context of cardio-oncology are limited, we also draw upon clinical and preclinical studies, which have examined these pathways in other relevant pathologies.