Peoples et al. Experimental & Molecular Medicine (2019) 51:162 https://doi.org/10.1038/s12276-019-0355-7 Experimental & Molecular Medicine REVIEW ARTICLE Open Access Mitochondrial dysfunction and oxidative stress in heart disease Jessica N. Peoples1,AnitaSaraf2, Nasab Ghazal1,TylerT.Pham3 and Jennifer Q. Kwong1 Abstract Beyond their role as a cellular powerhouse, mitochondria are emerging as integral players in molecular signaling and cell fate determination through reactive oxygen species (ROS). While ROS production has historically been portrayed as an unregulated process driving oxidative stress and disease pathology, contemporary studies reveal that ROS also facilitate normal physiology. Mitochondria are especially abundant in cardiac tissue; hence, mitochondrial dysregulation and ROS production are thought to contribute significantly to cardiac pathology. Moreover, there is growing appreciation that medical therapies designed to mediate mitochondrial ROS production can be important strategies to ameliorate cardiac disease. In this review, we highlight evidence from animal models that illustrates the strong connections between mitochondrial ROS and cardiac disease, discuss advancements in the development of mitochondria-targeted antioxidant therapies, and identify challenges faced in bringing such therapies into the clinic. Introduction permeability transition pore (MPTP), mitochondrial dys- Reactive oxygen species (ROS), including the super- function, and cell death2. Indeed, dysregulated ROS pro- oxide anion, the hydroxyl radical, and hydrogen peroxide, duction and oxidative stress have been implicated in a are critical signaling molecules with important roles in host of cardiac diseases, including cardiac hypertrophy, both cardiac physiology and disease. Both cytosolic heart failure (HF), cardiac ischemia–reperfusion injury sources, including NADPH oxidases (NOX), xanthine (IRI), and diabetic cardiomyopathy (discussed in greater – oxidase, cyclooxygenases, and cytochrome P450 enzymes, detail in refs 3 6). and mitochondrial sources, including the respiratory Given the important roles of ROS signaling in both chain, monoamine oxidases (MAOs), p66shc, and NOX4, cardiac physiology and disease, ROS signaling is tightly contribute to the intracellular ROS pool. Under physio- regulated, and intracellular redox homeostasis must be logical conditions, cardiac ROS signaling regulates heart maintained to ensure that physiological ROS signaling can development and cardiomyocyte maturation, cardiac cal- occur while pathological ROS signaling pathways are not cium handling, excitation contraction coupling, and vas- activated. Intracellular ROS levels are held in check by an cular tone (reviewed in greater detail in ref. 1). However, intricate array of antioxidant defense systems that include pathological conditions of unregulated ROS production superoxide dismutases, catalase, the glutathione perox- leading to elevated ROS levels can result in oxidative idase/reductase (GSH-PX) system, and the peroxiredoxin/ stress through oxidative damage to DNA, proteins, and thioredoxin (PRX/Trx) system. Similar to conditions of lipids, as well as activation of the mitochondrial- unregulated ROS production, an impairment in cellular antioxidant defenses and ROS scavenging can also lead to – cardiac dysfunction7 11. Correspondence: Jennifer Q. Kwong ([email protected]) In light of the strong connections between ROS and 1Department of Pediatrics, Division of Cardiovascular Biology, Emory University cardiac disease, there has been intense interest in deci- School of Medicine, Atlanta, GA 30322, USA phering the mechanisms regulating cardiac ROS pro- 2Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30322, USA duction and detoxification, as well as in developing Full list of author information is available at the end of the article. © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Korean Society for Biochemistry and Molecular Biology Peoples et al. Experimental & Molecular Medicine (2019) 51:162 Page 2 of 13 therapies to limit ROS production and enhance ROS ROS production within each complex and the mechan- detoxification as a means to ameliorate cardiac disease isms by which they are produced are not fully elucidated, outcomes. Importantly, there has been increasing evi- complexes I (NADH:ubiquinone oxidoreductase) and III dence that strategies targeting global ROS activity, such as (ubiquinol:cytochrome c oxidoreductase) are recognized trials with systemic administration of the antioxidants as the major sources of ROS within the respiratory chain. vitamin C and vitamin E, have fallen short in their ability For complex I, superoxide production has been suggested to mitigate cardiac disease12, while specific targeting of to stem from either reduced flavin mononucleotide14 or the mitochondrial ROS pool may be highly beneficial13.In the N-1a and N-1b iron–sulfur clusters15. For complex III, support of a central role for mitochondria-derived ROS in superoxide has been suggested to be generated at the cardiac disease pathogenesis, there has been strong sup- ubiquinol oxidation site16,17. port from in vivo models that link dysregulation of In addition to the respiratory chain, a number of addi- mitochondrial ROS production and/or impairment in tional mitochondria-localized proteins have been shown mitochondrial ROS scavenging to cardiac dysfunction. to contribute to the mitochondrial ROS pool. These In this review, we discuss intracellular sources of ROS, proteins include p66shc,MAOs, and NOX4 (Fig. 1). the role of oxidative stress in heart disease, evidence P66shc is a member of the Shc (Src homology 2 domain linking mitochondrial ROS to cardiac disease, the efficacy and collagen-homology region) family of cytosolic adaptor of ROS-based therapeutics in the heart, and the emerging proteins. Unlike its molecular relatives p52Shc and frontier of mitochondria-targeted antioxidant therapies p46Shc, which regulate Ras signaling, p66shc has been and their application to cardiac disease. found to play an important role in oxidative stress sig- naling. As a cytosolic protein that partially localizes to the Mitochondrial sources of ROS mitochondrial intermembrane space18, p66shc con- The mitochondrial respiratory chain is central to energy tributes to mitochondrial ROS production by oxidizing production as it couples electron transfer between cytochrome c and stimulating hydrogen peroxide respiratory chain complexes to proton transport across production19. the mitochondrial inner membrane to generate the elec- The MAO isoforms A and B (MAO-A and MAO-B) trochemical gradient required for ATP synthesis. In have also been identified as important sources of mito- addition to being essential for energy production, the chondrial hydrogen peroxide. Localized to the mito- respiratory chain is also the predominant source of chondrial outer membrane, MAOs utilize the cofactor intracellular ROS, which are produced as a byproduct of FAD to catalyze the oxidative degradation of mono- electron transfer (Fig. 1). Although the precise sites of amines, such as epinephrine and norepinephrine, into hydrogen peroxide and aldehydes. Importantly, both MAO-A and MAO-B are expressed in the heart and, as H O H O NE/EPI 2 2 2 2 described in greater detail below, have been shown to play MAO-A/B Cytosol an important role in HF and cardiac IRI. NOXs are a family of proteins involved in intracellular ROS production and catalyze the transfer of NADPH to H O molecular oxygen to generate superoxide and hydrogen 2 2 H2O2 H O 2 2 peroxide. Of particular interest is NOX4, which partially localizes to the mitochondrial inner membrane in cardi- - O2 O O -O 2 p66Shc 20–22 2 2 V omyocytes and renal cells . NOX4 has been shown to Cyto c Intermembrane space be a source of mitochondrial superoxide and hydrogen I II III IV NOX4 peroxide as NOX4 knockdown reduces the production of Q Matrix both ROS species22,23. More recently, NOX4 activity has been found to be regulated by ATP, suggesting that H O -O 2 2 2 NOX4 can couple mitochondrial oxidative stress signaling Fig. 1 Mitochondrial ROS generation. Respiratory chain complexes I to a cellular energetic state22. − and III (orange) generate superoxide (O2 ) and hydrogen peroxide (H2O2) from molecular oxygen (O2) within the mitochondrial Mitochondrial ROS scavenging systems intermembrane space. p66Shc (blue), in association with cytochrome c, participates in ROS signaling by producing hydrogen peroxide also To regulate oxidative stress created by mitochondrial within the intermembrane space. NADPH oxidase 4 (NOX4; red) ROS, mitochondria employ an intricate network of ROS − localizes