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Mitochondria-targeted therapies, such as Elamipretide (SS-31, MTP-131, Bendavia), have consequently emerged as a topic of scientific and clinical interest. Elamipretide has a unique structure allowing for uptake in a variety of cell types and highly selective mitochondrial targeting. This mitochondria-targeting tetrapeptide selectively binds cardiolipin (CL), a lipid found in the inner mitochondrial membrane, thus stabilizing mitochondrial cristae structure, reducing oxidative stress, and enhancing adenosine triphosphate (ATP) production. Preclinical studies have demonstrated the protective and restorative efficacy of Elamipretide in models of heart failure, neurodegeneration, ischemia\u2013reperfusion injury, metabolic syndromes, and muscle atrophy and weakness. Clinical trials such as PROGRESS-HF, TAZPOWER, MMPOWER-3, and ReCLAIM elaborate on preclinical findings and highlight the significant therapeutic potential of Elamipretide. Further research may expand its application to other diseases involving mitochondrial dysfunction as well as investigate long-term efficacy and safety of the drug. The following review synthesizes current knowledge of the structure, mechanisms of action, and the promising therapeutic role of Elamipretide in stabilizing mitochondrial fitness, improving mitochondrial bioenergetics, and minimizing oxidative stress.<\/jats:p>","DOI":"10.3390\/ijms26030944","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T09:01:13Z","timestamp":1737622873000},"page":"944","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":114,"title":["Elamipretide: A Review of Its Structure, Mechanism of Action, and Therapeutic Potential"],"prefix":"10.3390","volume":"26","author":[{"given":"Cheryl","family":"Tung","sequence":"first","affiliation":[{"name":"Department of Medicine, (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York City, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fahimeh","family":"Varzideh","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York City, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Farroni","sequence":"additional","affiliation":[{"name":"Department of Medicine, (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York City, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Mone","sequence":"additional","affiliation":[{"name":"Department of Medicine, (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York City, NY 10461, USA"},{"name":"Montevergine Clinic, Mercogliano, 83013 Avellino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urna","family":"Kansakar","sequence":"additional","affiliation":[{"name":"Department of Medicine, (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York City, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislovas S.","family":"Jankauskas","sequence":"additional","affiliation":[{"name":"Department of Medicine, (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York City, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7231-375X","authenticated-orcid":false,"given":"Gaetano","family":"Santulli","sequence":"additional","affiliation":[{"name":"Department of Medicine, (Division of Cardiology), Wilf Family Cardiovascular Research Institute, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York City, NY 10461, USA"},{"name":"Department of Molecular Pharmacology, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York City, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"29789","DOI":"10.1039\/D4RA05517A","article-title":"Discovery of novel SS-31 (d-Arg-dimethylTyr-Lys-Phe-NH(2)) derivatives as potent agents to ameliorate inflammation and increase mitochondrial ATP synthesis","volume":"14","author":"Li","year":"2024","journal-title":"RSC Adv."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2669","DOI":"10.1007\/s11095-011-0476-8","article-title":"Novel therapies targeting inner mitochondrial membrane\u2014From discovery to clinical development","volume":"28","author":"Szeto","year":"2011","journal-title":"Pharm. 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