A large body of evidence indicates that mitochondrial dysfunction has a major role in the pathogenesis of multiple cardiovascular disorders. Over the past 2 decades, extraordinary efforts have been focused on the development of agents that specifically target mitochondria for the treatment of cardiovascular disease. Despite such an intensive wave of investigation, no drugs specifically conceived to modulate mitochondrial functions are currently available for the clinical management of cardiovascular disease. In this Review, we discuss the therapeutic potential of targeting mitochondria in patients with cardiovascular disease, examine the obstacles that have restrained the development of mitochondria-targeting agents thus far, and identify strategies that might empower the full clinical potential of this approach.
Mitochondrial dysfunction is involved in the pathogenesis of multiple cardiovascular disorders, including myocardial infarction, cardiomyopathies of various aetiologies, arrhythmias, hypertension, and atherosclerosis.
Mitochondria are essential for the physiological activity of the cardiovascular system owing to their crucial role in bioenergetic and anabolic metabolism and their central position in intracellular Ca2+ fluxes.
In addition to losing their physiological functions, damaged mitochondria actively drive inflammatory responses and waves of regulated cell death that contribute to the pathogenesis of cardiovascular disease.
An intensive wave of investigation attempted to develop mitochondria-targeting agents for preventing or treating cardiovascular disorders in patients, with rather dismal results.
Molecules with improved pharmacological features, precise mechanistic insights into mitochondrial processes, and reconsidering the pathogenesis of some cardiovascular disorders are instrumental for the development of mitochondria-targeting agents with clinical use.
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The authors apologize to the authors of several high-quality articles on mitochondria as a therapeutic target for cardiovascular disorders that could not be discussed and cited owing to space limitations. M.R.W. is supported by a Polish National Science Centre grant (UMO-2014/15/B/NZ1/00490). D.A.S. receives support from the Glenn Foundation for Medical Research, the Sinclair Gift Fund, and the US NIH/National Institute on Aging (R01 AG028730 and R01 DK100263). G.K. receives support from the Ligue Nationale contre le Cancer Comité de Charente-Maritime (équipe labellisée); the Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; the Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), the Fondation pour la Recherche Médicale (FRM); a donation by Elior; the European Commission (ArtForce); the European Research Council (ERC); Fondation Carrefour; the Institut National du Cancer (INCa); INSERM (HTE); the Institut Universitaire de France; the LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). P.P. is grateful to Camilla degli Scrovegni for continuous support; P.P. receives support from the Italian Ministry of Education, the University and Research; Telethon (GGP15219/B); the Italian Association for Cancer Research (AIRC; IG-18624); and by local funds from the University of Ferrara (Ferrara, Italy). L.G. is supported by a start-up grant from the Department of Radiation Oncology at Weill Cornell Medicine (New York, NY, USA) and by donations from Sotio a.s. (Prague, Czech Republic), Phosplatin (New York, NY, USA), and the Luke Heller TECPR2 Foundation (Boston, MA, USA).
Nature Reviews Cardiology thanks R. Gottlieb, M. Hirschey, M. Sack, and the other anonymous reviewer(s) for their contribution to the peer review of this work.
D.A.S. is a consultant to and inventor on patents licensed to CohBar, GlaxoSmithKline, Jumpstart Fertility, Liberty Biosecurity, Life Biosciences, and MetroBiotech. The other authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Regulated cell death
(RCD). A form of cell death that relies on the activation of a genetically encoded machinery and which, therefore, can be retarded or accelerated with specific pharmacological or genetic interventions.
Evolutionarily conserved cellular process that culminates with the lysosomal degradation of ectopic, supernumerary, dysfunctional, or potentially dangerous cytoplasmic entities (of endogenous or exogenous derivation).
Biochemical pathway whereby fatty acids are converted into acetyl-CoA, which enters the TCA cycle, and NADH and FADH2, which fuel oxidative phosphorylation.
Biochemical pathway whereby ketone bodies are converted into acetyl-CoA, which enters the TCA cycle, and NADH, which fuels oxidative phosphorylation.
- Folate cycle
Biochemical pathway catalysing the cyclic conversion of tetrahydrofolate, 10-formyl-tetrahydrofolate (which feeds into purine synthesis), 5,10-methylenetetrahydrofolate, and 5-methyl-tetrahydrofolate (which feeds into methionine metabolism).
- Mitochondrial permeability transition
(MPT). Rapid loss of the ionic barrier function of the inner mitochondrial membrane, culminating in mitochondrial breakdown and regulated necrosis.
Iron-binding plasma glycoprotein that controls the level of free iron ions in biological fluids.
- Cerebral cavernous malformations
Cerebrovascular disease characterized by enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral haemorrhages.
- Histone deacetylase inhibitor
Member of a fairly new class of targeted anticancer agents that operate by derepressing histone acetylation, resulting in the epigenetic reconfiguration of multiple transcriptional modules.
Form of RCD that depends on mixed lineage kinase domain-like protein (MLKL), receptor-interacting serine/threonine-protein kinase 3 (RIPK3), and, at least in some settings, the kinase activity of the RIPK3 homologue RIPK1.
Iron-dependent form of RCD that obligatorily relies on lipid peroxidation and is tonically inhibited by glutathione peroxidase 4 (GPx4).
- Damage-associated molecular patterns
(DAMPs). Endogenous molecules that exert potent immunomodulatory functions upon binding to cellular receptors that evolved to control microbial pathogens.
Supramolecular complex containing caspase 1 (CASP1), which, among other functions, catalyses the proteolytic processing of IL-1β and IL-18, thereby enabling their release in a bioactive form.
- γδ T lymphocytes
Small subsets of T cells expressing a rather invariant variant of the T cell receptor and mostly operating at the interface between innate and adaptive immunity.
Large family of arachidonic acid derivatives involved in the regulation of multiple biological processes, including the recruitment and activation of immune cells.
Form of RCD initiated by extracellular or intracellular cues that is precipitated by the sequential activation of various members of the caspase protein family.
Necrotic variant of RCD driven by PARP1 hyperactivation and precipitated by the consequent bioenergetic catastrophe coupled to enzymatic DNA degradation.
(miRNAs). Small non-coding RNA molecules that regulate the expression of target genes at the transcriptional or post-transcriptional level.
Particle of 1–100 nm in size surrounded by an interfacial layer consisting of ions, inorganic molecules, or organic molecules that determines the biological and biophysical properties of the particle.
- Mitochondrial transmembrane potential
(Δψm). Electrochemical gradient built across the inner mitochondrial membrane by the respiratory chain. The Δψm drives multiple mitochondrial functions, including ATP synthesis and protein transport.
Term generally referring to the metal-catalysed oxidation (primary carbonylation) or addition of reactive aldehydes (secondary carbonylation) to amino acid side chains.
- Pharmacological audit trail
Rational framework to guide the development of novel therapeutic agents that involves assessing the risk of failure at any specific stage.
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Bonora, M., Wieckowski, M.R., Sinclair, D.A. et al. Targeting mitochondria for cardiovascular disorders: therapeutic potential and obstacles. Nat Rev Cardiol 16, 33–55 (2019). https://doi.org/10.1038/s41569-018-0074-0
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