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

Abstract

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.

Keywords: DAMPs; cardio-oncology; cardiotoxicity; chemotherapy; mitochondria.

Figure 1.

Graphical illustration of selected anticancer therapy (CTx) drugs illustrating their mitochondrial pathophysiological signaling pathways and some of the associated cardiotoxic outcomes. CTx agents work through different mechanisms and induce mitochondrial dysfunction through various pathophysiological pathways. This is graphical illustration of complex pathogenic pathways using selected examples from literature identified in our article. It is not meant to be an exhaustive depiction of all existing pathways but rather presents some key examples. Image created with Rawgraphs.io and published with permission. ETC, electron transport chain; MACE, major adverse cardiovascular events; ROS, reactive oxygen species; TKI, tyrosine kinase inhibitor.

Figure 2.

Anticancer therapy (CTx) alters intracellular mitochondrial signaling. Several CTx agents induce mitochondrial dysfunction by promoting mitochondrial DNA (mtDNA) damage, suppressing mitochondrial metabolism, altering mitochondrial Ca²⁺ homeostasis, increasing production of reactive oxygen species (ROS), altering mitochondrial-nuclear communication, and/or inducing epigenetic and transcriptional remodeling. Mitochondria also play a role in CTx-induced apoptosis through release of cytochrome-c (Cyt c) and second mitochondria-derived activator of caspases (SMAC) and activation of apoptosomes. Nucleic acids in the cytosol, including _mtRNA and _mtDNA, activate innate immune cascades that ultimately promote inflammation. Image created with Biorender.com and published with permission. AIM2, absent-in melanoma 2; cGAS, GMP-AMP synthase; IRF3, interferon regulatory factor 3; RIG-I, retinoic acid-inducible gene I; STING, stimulator of interferon genes.

Figure 3.

Systemic mitochondrial signaling may promote cardiovascular inflammation following anticancer therapy (CTx). CTx-induced cellular stress and death promote the release of damage-associated molecular patterns (DAMPs). DAMPs released from mitochondria include cell-free mitochondrial DNA (mtDNA), ATP, formyl peptides, and mitochondrial membrane fractions, among others. Circulating mitochondrial DAMPs are recognized by pattern recognition receptors of the innate immune system, including Toll-like receptors (TLRs), purinergic receptors, formyl peptide receptors (FPRs), and nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs). Activation of innate immune receptors on immune cells, cardiomyocytes, and vascular cells promotes cardiovascular inflammation that may play a role in CTx-induced cardiotoxicity. Image created with Biorender.com and published with permission.