{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T08:42:24Z","timestamp":1793349744337,"version":"4.5.0"},"reference-count":135,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Top Talents Project of Gansu Province","award":["2023-9"],"award-info":[{"award-number":["2023-9"]}]},{"name":"the Science and Technology Innovation Talent Program of Chengguan District","award":["2025KJRC00087"],"award-info":[{"award-number":["2025KJRC00087"]}]},{"name":"the Top Talents Project of Gansu Province","award":["2024-96"],"award-info":[{"award-number":["2024-96"]}]},{"name":"the Natural Science Foundation of Gansu Province","award":["23JRRA677"],"award-info":[{"award-number":["23JRRA677"]}]},{"name":"the Young Scientists Fund of the National Natural Science Foundation of China","award":["12405395"],"award-info":[{"award-number":["12405395"]}]},{"name":"the Longyuan Youth Talent Program of Gansu Province","award":["2022-5"],"award-info":[{"award-number":["2022-5"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer\u2019s disease, Parkinson\u2019s disease, and Huntington\u2019s disease\u2014the major protagonists of NDs\u2014while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K\/AKT\/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials.<\/jats:p>","DOI":"10.3390\/biology15020189","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T11:27:58Z","timestamp":1768908478000},"page":"189","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases"],"prefix":"10.3390","volume":"15","author":[{"given":"Yanyu","family":"Bao","sequence":"first","affiliation":[{"name":"Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China"},{"name":"State Key Laboratory of Heavy Ion Science and Technology, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoying","family":"Miao","sequence":"additional","affiliation":[{"name":"Gansu Provincial Maternity and Child-Care Hospital\/Gansu Provincial Central Hospital, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nannan","family":"He","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The Second Hospital of Lanzhou University, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingting","family":"Bao","sequence":"additional","affiliation":[{"name":"Medical College, Northwest Minzu University, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Shi","sequence":"additional","affiliation":[{"name":"School of Biopharmaceutical and Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuilan","family":"Hu","sequence":"additional","affiliation":[{"name":"Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China"},{"name":"State Key Laboratory of Heavy Ion Science and Technology, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1048-2758","authenticated-orcid":false,"given":"Xiongxiong","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China"},{"name":"State Key Laboratory of Heavy Ion Science and Technology, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7180-639X","authenticated-orcid":false,"given":"Bing","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute for Radiological Science, National Institutes for Quantum Science and Technology (QST), Chiba 263-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9046-3142","authenticated-orcid":false,"given":"Chao","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China"},{"name":"State Key Laboratory of Heavy Ion Science and Technology, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e70519","DOI":"10.1002\/alz.70519","article-title":"Mitochondrial complex I deficiency induces Alzheimer\u2019s disease-like signatures that are reversible by targeted therapy","volume":"21","author":"Gao","year":"2025","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1242\/dmm.026294","article-title":"Mitochondrial dynamics in Parkinson\u2019s disease: A role for \u03b1-synuclein?","volume":"10","author":"Falzone","year":"2017","journal-title":"Dis. 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