Current Advances of Mitochondrial Dysfunction and Cardiovascular Disease and Promising Therapeutic Strategies
2023; Elsevier BV; Volume: 193; Issue: 10 Linguagem: Inglês
10.1016/j.ajpath.2023.06.013
ISSN1525-2191
AutoresDexiang Xia, Yue Liu, Peng Wu, Dangheng Wei,
Tópico(s)ATP Synthase and ATPases Research
ResumoMitochondria are cellular power stations and essential organelles for maintaining cellular homeostasis. Dysfunctional mitochondria have emerged as a key factor in the occurrence and development of cardiovascular disease. This review focuses on advances in the relationship between mitochondrial dysfunction and cardiovascular diseases such as atherosclerosis, heart failure, myocardial ischemia reperfusion injury, and pulmonary arterial hypertension. The clinical value and challenges of mitochondria-targeted strategies, including mitochondria-targeted antioxidants, mitochondrial quality control modulators, mitochondrial function protectors, mitochondrial biogenesis promoters, and recently developed mitochondrial transplants, are also discussed. Mitochondria are cellular power stations and essential organelles for maintaining cellular homeostasis. Dysfunctional mitochondria have emerged as a key factor in the occurrence and development of cardiovascular disease. This review focuses on advances in the relationship between mitochondrial dysfunction and cardiovascular diseases such as atherosclerosis, heart failure, myocardial ischemia reperfusion injury, and pulmonary arterial hypertension. The clinical value and challenges of mitochondria-targeted strategies, including mitochondria-targeted antioxidants, mitochondrial quality control modulators, mitochondrial function protectors, mitochondrial biogenesis promoters, and recently developed mitochondrial transplants, are also discussed. Over the past decades, age-standardized death rates from cardiovascular disease (CVD) have declined substantially through primary and secondary prevention measures.1Amini M. Zayeri F. Salehi M. Trend analysis of cardiovascular disease mortality, incidence, and mortality-to-incidence ratio: results from global burden of disease study 2017.BMC Public Health. 2021; 21: 401Crossref PubMed Scopus (191) Google Scholar However, CVD is still the leading cause of death worldwide, posing a serious threat to human life and health. Between 1990 and 2019, the overall number of people with CVD nearly doubled, from 271 million to 523 million, and the number of deaths from CVD increased steadily from 12.1 million to 18.6 million.2Roth G.A. Mensah G.A. Johnson C.O. Addolorato G. Ammirati E. Baddour L.M. et al.GBD-NHLBI-JACC Global Burden of Cardiovascular Diseases Writing GroupGlobal burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study.J Am Coll Cardiol. 2020; 76 ([Erratum appeared in J Am Coll Cardiol 2021;77:1958-1959]): 2982-3021Crossref PubMed Scopus (3321) Google Scholar According to the World Health Organization, nearly 23.6 million people will die of CVD by 2030.3Cannon B. Cardiovascular disease: biochemistry to behaviour.Nature. 2013; 493: S2-S3Crossref PubMed Scopus (62) Google Scholar Mitochondria, semi-autonomous organelles with their own genetic and protein synthesis system, are well known as cellular power stations. There is convincing evidence that mitochondrial dysfunction contributes to CVD. The current article discusses advances in mitochondrial dysfunction in CVD and potential therapeutic strategies targeting mitochondrial dysfunction. As semi-autonomous organelles, mitochondria have their own genetic and protein synthesis system. Mitochondrial DNA (mtDNA) is a double-stranded molecule with a total length of 16,569 bp. It encodes 13 oxidative phosphorylation complex polypeptides, including seven subunits of complex I, one subunit of complex III, three subunits of complex IV, and two subunits of complex V. Complexes I to IV locate at the inner mitochondrial membrane, and they pump H+ from the matrix side of the inner membrane into the intermembrane space to create mitochondrial membrane potential (MMP). These H+ then enter the matrix through the proton channels to produce ATP (Figure 1). Under physiological conditions, about 0.2% to 2% of electrons leak from the electron transport chain (ETC) and are transported to generate reactive oxygen species (ROS) at complexes I and III (Figure 1). Interestingly, mitochondria not only serve as cellular power stations to control cells' life activities but also play a central role in regulating various biologic processes. For example, mitochondrial components and metabolites such as nucleic acids, ATP, and proteins act as damage-associated molecular patterns to activate pattern recognition receptors on the surface of inflammatory cells, thereby promoting inflammation (Figure 1). Mechanically, mtDNA acts as damage-associated molecular patterns to promote inflammation by activating cyclic GMP–AMP synthase/stimulator of interferon response cGAMP interactor 1 signaling, inflammasome signaling, and Toll-like receptor 9.4Marchi S. Guilbaud E. Tait S.W.G. Yamazaki T. Galluzzi L. Mitochondrial control of inflammation.Nat Rev Immunol. 2022; 23: 159-173Crossref PubMed Scopus (103) Google Scholar In addition, other mitochondrial components and products such as cytochrome c, cardiolipin, N-formyl peptides, ATP, and heme have been shown to promote inflammation. In cells, strict quality control guarantees the normal physiological function of mitochondria (Figure 1). The proteome quality control system of mitochondria ensures that protein import, folding, and degradation are precise. Mitochondrial fission maintains the number and distribution of mitochondria, and mitochondrial fusion maintains normal mitochondrial function through exchanging contents from fused mitochondria. Mitophagy selectively removes dysfunctional or redundant mitochondria through the ubiquitin- or receptor-mediated pathway. Studies have shown that mitochondrial spheroid responds to mitochondrial oxidation independently of mitophagy, acting as a novel mitochondrial quality control (MQC) mechanism.5Ding W.-X. Li M. Biazik J.M. Morgan D.G. Guo F. Ni H.-M. Goheen M. Eskelinen E.-L. Yin X.-M. Electron microscopic analysis of a spherical mitochondrial structure.J Biol Chem. 2012; 287: 42373-42378Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar The ETC conducts electron transfer to generate ATP during oxidative phosphorylation. In myocardial ischemia, damaged ETC reduces cell death by decreasing cytochrome c release and activating calpain 1 through calcium overload and oxidative stress.6Chen Q. Thompson J. Hu Y. Lesnefsky E.J. The mitochondrial electron transport chain contributes to calpain 1 activation during ischemia-reperfusion.Biochem Biophys Res Commun. 2022; 613: 127-132Crossref PubMed Scopus (4) Google Scholar The activation of calpain 1 mediates vascular remodeling and fibrosis in pulmonary arterial hypertension (PAH) via hypoxia-inducible factor-1α and participates in Coxsackievirus B3–induced myocardial injury by mitochondrial ROS-induced NOD-, LRR-, and pyrin domain–containing 3 inflammasome activation.7Deng H. Tian X. Sun H. Liu H. Lu M. Wang H. Calpain-1 mediates vascular remodelling and fibrosis via HIF-1[alpha] in hypoxia-induced pulmonary hypertension.J Cell Mol Med. 2022; 26: 2819-2830Crossref PubMed Scopus (0) Google Scholar,8Liu X. Li M. Chen Z. Yu Y. Shi H. Yu Y. Wang Y. Chen R. Ge J. Mitochondrial calpain-1 activates NLRP3 inflammasome by cleaving ATP5A1 and inducing mitochondrial ROS in CVB3-induced myocarditis.Basic Res Cardiol. 2022; 117: 40Crossref PubMed Scopus (19) Google Scholar Therefore, blocking ETC can enhance the tricarboxylic acid cycle and fatty acid oxidation (FAO) to reduce myocardial ischemia/reperfusion injury (MIRI). In PAH rats, the activities of complexes I and III are decreased, leading to metabolic shifts, a hallmark of PAH pathology.9Rafikov R. Sun X. Rafikova O. Meadows M.L. Desai A.A. Khalpey Z. Yuan J.X.-J. Fineman J.R. Black S.M. Complex I dysfunction underlies the glycolytic switch in pulmonary hypertensive smooth muscle cells.Redox Biol. 2015; 6: 278-286Crossref PubMed Google Scholar,10Rafikova O. Srivastava A. Desai A.A. Rafikov R. Tofovic S.P. Recurrent inhibition of mitochondrial complex III induces chronic pulmonary vasoconstriction and glycolytic switch in the rat lung.Respir Res. 2018; 19: 69Crossref PubMed Scopus (25) Google Scholar In patients with atrial fibrillation (AF), the activity of complexes I and II is decreased due to the reduced expression of the complex I subunit NDUFB8 and posttranslational modifications of complex II subunits.11Emelyanova L. Ashary Z. Cosic M. Negmadjanov U. Ross G. Rizvi F. Olet S. Kress D. Sra J. Tajik A.J. Holmuhamedov E.L. Shi Y. Jahangir A. Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation.Am J Physiol Heart Circ Physiol. 2016; 311: H54-H63Crossref PubMed Scopus (37) Google Scholar In the ischemic heart, the activity of complexes I to IV and the expression of ETC proteins is decreased due to the increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which is improved after blood flow is recovered.12Lee H.-L. Chen C.-L. Yeh S.T. Zweier J.L. Chen Y.-R. Biphasic modulation of the mitochondrial electron transport chain in myocardial ischemia and reperfusion.Am J Physiol Heart Circ Physiol. 2012; 302: H1410-H1422Crossref PubMed Scopus (63) Google Scholar These data show that the decreased activity of ETC complexes is strongly linked to the development of CVD. Under physiological conditions, about 0.2% to 2% of electrons leak from ETC. When the ETC is impaired, a large number of electrons leak out to generate large amounts of ROS. ROS contribute to the occurrence and development of CVD through the following pathways. The first pathway is uncoupling of nitric oxide synthase (NOS): during the conversion of arginine to l-citrulline to produce NO, various cofactors, notably tetrahydrobiopterin, are required to stabilize NOS. ROS can deplete tetrahydrobiopterin and directly bind to NO to form ONOO−, leading to the uncoupling of NOS. This process has been considered as a hallmark of CVD. A second pathway is inflammation: ROS up-regulates pro-inflammatory factors such as IL-1β, IL-6, and tumor necrosis factor-α; activates the NOD-, LRR-, and pyrin domain–containing 3 inflammasome and inflammation; and then promotes the development of CVD. The final pathway is a vicious circle: excessive ROS inhibit mitochondrial Na+/Ca2+ exchange and damage mtDNA, resulting in mitochondrial dysfunction, which in turn leads to more ROS production. mtDNA is susceptible to damage by ROS compared with nuclear DNA due to its lack of histone protection and its proximity to the ETC. A prospective, population-based cohort analysis of 21,870 participants found that the reduction of mtDNA copy numbers is an independent risk factor for cardiovascular events.13Ashar F.N. Zhang Y. Longchamps R.J. Lane J. Moes A. Grove M.L. Mychaleckyj J.C. Taylor K.D. Coresh J. Rotter J.I. Boerwinkle E. Pankratz N. Guallar E. Arking D.E. Association of mitochondrial DNA copy number with cardiovascular disease.JAMA Cardiol. 2017; 2: 1247-1255Crossref PubMed Scopus (161) Google Scholar In addition, mtDNA copy numbers are inversely associated with the risk of heart failure (HF) events, the occurrence of adverse stroke events, and the risk of AF. Mechanically, mtDNA damage induces excessive ROS to promote mitochondrial dysfunction, resulting in more serious mtDNA damage, thus forming a vicious cycle. Consistent with this notion, mtDNA mutant mice at a later stage exhibit higher levels of ROS than at an early stage.14Logan A. Shabalina I.G. Prime T.A. Rogatti S. Kalinovich A.V. Hartley R.C. Budd R.C. Cannon B. Murphy M.P. In vivo levels of mitochondrial hydrogen peroxide increase with age in mtDNA mutator mice.Aging Cell. 2014; 13: 765-768Crossref PubMed Scopus (84) Google Scholar Moreover, mtDNA damage reduces ATP synthesis and the MMP, which increases the opening of mitochondrial permeability transition pore (mPTP) and apoptosis. Furthermore, mtDNA, as damage-associated molecular patterns, activate cyclic GMP–AMP synthase/stimulator of interferon response cGAMP interactor 1 and Toll-like receptor 9 signaling, promoting cardiovascular inflammation and accelerating progression of CVD. Notably, mtDNA mutant mice exhibit hyperlipidemia, as well as decreased subcutaneous fat and body weight, suggesting that mtDNA damage leads to the systemic metabolic switch,15Trifunovic A. Wredenberg A. Falkenberg M. Spelbrink J.N. Rovio A.T. Bruder C.E. Bohlooly-Y M. Gidlöf S. Oldfors A. Wibom R. Törnell J. Jacobs H.T. Larsson N.-G. Premature ageing in mice expressing defective mitochondrial DNA polymerase.Nature. 2004; 429: 417-423Crossref PubMed Scopus (2113) Google Scholar which might be a potential way to promote the progression of CVD. Mitophagy is divided into ubiquitin-mediated mitophagy and receptor-mediated mitophagy. Mitophagy and mitochondrial function are impaired in patients with HF and in HF mouse models. When mitophagy is restored, the damaged mitochondria are removed, and mitochondrial function is improved, contributing to a positive effect on HF.16Wang B. Nie J. Wu L. Hu Y. Wen Z. Dong L. Zou M.-H. Chen C. Wang D.W. AMPK[alpha]2 protects against the development of heart failure by enhancing mitophagy via PINK1 phosphorylation.Circ Res. 2018; 122: 712-729Crossref PubMed Scopus (0) Google Scholar In addition, Parkin–/– mice develop pathologic cardiac hypertrophy and left ventricular dysfunction as early as 2 months of age, accompanied by mitochondrial dysfunction and enhanced oxidative stress.17Billia F. Hauck L. Konecny F. Rao V. Shen J. Mak T.W. PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function.Proc Natl Acad Sci U S A. 2011; 108: 9572-9577Crossref PubMed Scopus (279) Google Scholar Similarly, the administration of cytosolic p53 (a Parkin inhibitor) in mice inhibits mitophagy and leads to myocardial mitochondrial dysfunction.18Hoshino A. Mita Y. Okawa Y. Ariyoshi M. Iwai-Kanai E. Ueyama T. Ikeda K. Ogata T. Matoba S. Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart.Nat Commun. 2013; 4: 2308Crossref PubMed Scopus (394) Google Scholar Moreover, Parkin–/– mice are more prone to myocardial infarction and have lower survival rates than wild-type mice,19Kubli D.A. Zhang X. Lee Y. Hanna R.A. Quinsay M.N. Nguyen C.K. Jimenez R. Petrosyan S. Murphy A.N. Gustafsson A.B. Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction.J Biol Chem. 2013; 288: 915-926Abstract Full Text Full Text PDF PubMed Scopus (360) Google Scholar and Parkin-regulated mitophagy is impaired in aging hearts.20Gao B. Yu W. Lv P. Liang X. Sun S. Zhang Y. Parkin overexpression alleviates cardiac aging through facilitating K63-polyubiquitination of TBK1 to facilitate mitophagy.Biochim Biophys Acta Mol Basis Dis. 2021; 1867165997Crossref Scopus (11) Google Scholar These results suggest that impaired mitophagy leads to the accumulation of damaged mitochondria and the development of CVD. Mitochondrial fission is a process of self-maintenance and repair in which mitochondrial components are separated by asymmetric division and subsequently removed by mitophagy or by symmetric division into two functional mitochondria. In the myocardial infarction region, excessive mitochondrial fission is caused by hypoxia, and the inhibition of mitochondrial fission delays myocardial senescence and HF.21Nishimura A. Shimauchi T. Tanaka T. Shimoda K. Toyama T. Kitajima N. Ishikawa T. Shindo N. Numaga-Tomita T. Yasuda S. Sato Y. Kuwahara K. Kumagai Y. Akaike T. Ide T. Ojida A. Mori Y. Nishida M. Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence.Sci Signal. 2018; 11: eaat5185Crossref PubMed Scopus (76) Google Scholar This phenomenon is also observed in MIRI.22Sharp W.W. Fang Y.H. Han M. Zhang H.J. Hong Z. Banathy A. Morrow E. Ryan J.J. Archer S.L. Dynamin-related protein 1 (Drp1)-mediated diastolic dysfunction in myocardial ischemia-reperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission.FASEB J. 2014; 28: 316-326Crossref PubMed Scopus (266) Google Scholar Furthermore, right ventricular (RV) fibroblasts and myocytes in PAH exhibit excessive mitochondrial fission, whereas mitochondrial fission inhibitors (mdivi-1 and P110) protected RV function in RV-IR in a PAH rat model.23Tian L. Potus F. Wu D. Dasgupta A. Chen K.-H. Mewburn J. Lima P. Archer S.L. Increased Drp1-mediated mitochondrial fission promotes proliferation and collagen production by right ventricular fibroblasts in experimental pulmonary arterial hypertension.Front Physiol. 2018; 9: 828Crossref PubMed Scopus (49) Google Scholar Generally, GTPase dynamin-related protein 1 (Drp1) and dynamin proteins (DNM1, DNM2, and DNM3) are considered to be required in mitochondrial fission. However, recent studies showed that mitochondrial fission is impaired by the down-regulation of Drp1 instead of dynamins. When Drp1 is deficient, mitochondria become larger, and the expression of oxidative phosphorylation protein is reduced, resulting in impaired mitochondrial respiration and energy production.24Favaro G. Romanello V. Varanita T. Desbats M.A. Morbidoni V. Tezze C. Albiero M. Canato M. Gherardi G. De Stefani D. Mammucari C. Blaauw B. Boncompagni S. Protasi F. Reggiani C. Scorrano L. Salviati L. Sandri M. 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Mitochondrial fusion begins with the juxtaposition and tethering of adjacent mitochondria, in which mitofusin (Mfn) 1 and 2 and optic atrophy 1 (OPA1) are key mediators. OPA1 regulates apoptosis and mitochondrial respiration. The decreased expression of OPA1 leads to decreased nuclear antioxidant gene expression and mtDNA copy numbers in failing hearts.28Chen L. Gong Q. Stice J.P. Knowlton A.A. Mitochondrial OPA1, apoptosis, and heart failure.Cardiovasc Res. 2009; 84: 91-99Crossref PubMed Scopus (305) Google Scholar In addition, mitochondrial fusion proteins regulate calcineurin and Notch signaling, which are essential for cardiac differentiation.29Kasahara A. Cipolat S. Chen Y. Dorn 2nd, G.W. Scorrano L. 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