Mitochondrial dysfunction at the crossroad of cardiovascular diseases and cancer

Abstract

A large body of evidence indicates the existence of a complex pathophysiological relationship between cardiovascular diseases and cancer. Mitochondria are crucial organelles whose optimal activity is determined by quality control systems, which regulate critical cellular events, ranging from intermediary metabolism and calcium signaling to mitochondrial dynamics, cell death and mitophagy. Emerging data indicate that impaired mitochondrial quality control drives myocardial dysfunction occurring in several heart diseases, including cardiac hypertrophy, myocardial infarction, ischaemia/reperfusion damage and metabolic cardiomyopathies. On the other hand, diverse human cancers also dysregulate mitochondrial quality control to promote their initiation and progression, suggesting that modulating mitochondrial homeostasis may represent a promising therapeutic strategy both in cardiology and oncology. In this review, first we briefly introduce the physiological mechanisms underlying the mitochondrial quality control system, and then summarize the current understanding about the impact of dysregulated mitochondrial functions in cardiovascular diseases and cancer. We also discuss key mitochondrial mechanisms underlying the increased risk of cardiovascular complications secondary to the main current anticancer strategies, highlighting the potential of strategies aimed at alleviating mitochondrial impairment-related cardiac dysfunction and tumorigenesis. It is hoped that this summary can provide novel insights into precision medicine approaches to reduce cardiovascular and cancer morbidities and mortalities.

Keywords: Anticancer therapy; Cancer; Cardiotoxicity; Cardiovascular diseases; Mitochondrial dynamics; Mitochondrial dysfunction.

Fig. 1

General representation illustrating the consequences of the imbalance of mitochondrial dynamics, culminating in heart disease. See text for details. Drp1 dynamin-related protein 1, Mfn1 mitofusin 1, Mfn2 mitofusin 2, OPA1 optic atrophy 1, PINK1 PTEN-induced putative kinase 1, ΔΨm mitochondrial membrane potential

Fig. 2

Proposed mechanisms underlying the detrimental effects deriving from an imbalanced mitochondrial dynamic in the heart, with particular regard to the implication of Drp1, a protein playing a fundamental role in heart physiology and cardiomyocyte survival during normal conditions, but that it is upregulated during cardiac pathological conditions, resulting in excessive fission. See text for details. CVDs cardiovascular diseases, Drp1 dynamin-related protein 1, VDAC voltage-dependent anion channel

Fig. 3

Schematic representation of dysregulated mitochondrial dynamics in cancer suggesting that mitochondrial-dependent mechanisms may serve as potential pharmacological/therapeutic target aimed at restoring mitochondrial network and function. A brief representation is provided for the central role of mitochondria in the adverse cardiovascular events following anticancer therapies. See text for details. ATP5F1C ATP synthase F1 subunit gamma, Drp1 dynamin-related protein 1, IDH1 isocitrate dehydrogenase [NADP(+] 1, IDH2 isocitrate dehydrogenase [NADP(+)] 2, MASM7 mitofusin activator small molecules 7, Mdivi-1 mitochondrial division inhibitor-1, MFI8 mitochondrial fusion inhibitor 8, SLC25A8 UCP2 (uncoupling protein 2)