{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T10:26:12Z","timestamp":1787307972928,"version":"build-2736575974"},"reference-count":79,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sci.","Brain Sciences"],"abstract":"<jats:p>Background\/Objectives: Mitochondrial Complex V (Complex V [CX-V], or ATP synthase) is the terminal enzyme of oxidative phosphorylation and is responsible for the majority of cellular ATP production. An increasing body of evidence suggests that CX-V dysfunction may contribute to mitochondrial impairment observed in neurodegenerative disease. This review evaluated current research on the structure, regulation, and function of CX-V, examined the consequences of CX-V dysfunction, and assessed its proposed role in neurodegenerative disorders. Methods: A comprehensive review of the published literature was carried out, with emphasis on primary research investigating CX-V structure and function, inherited CX-V disorders, and experimental evidence linking CX-V dysfunction to neurodegenerative disease. The reviewed studies used a range of experimental approaches, including structural biology, biochemical studies, patient-derived cellular models, animal models and post-mortem human tissue. Results: Current evidence demonstrates that disruption of CX-V impairs ATP production, alters mitochondrial membrane potential, and oxidative phosphorylation, and that pathogenic variants cause primary mitochondrial disease. Across Alzheimer\u2019s disease, Parkinson\u2019s disease, Huntington\u2019s disease, amyotrophic lateral sclerosis\/frontotemporal dementia, glaucoma and inherited optic neuropathies, alterations in CX-V activity, regulation and structural integrity are consistently associated with mitochondrial dysfunction. Direct evidence supporting CX-V as a primary driver of neurodegeneration remains very limited, with many observations originating from broader studies of general mitochondrial dysfunction. Conclusions: CX-V dysfunction represents a recurring feature of mitochondrial impairment across a variety of neurodegenerative disorders and may exacerbate neuronal vulnerability by disrupting cellular bioenergetics. Current evidence indicates that CX-V may serve as a common downstream target of multiple pathological pathways rather than acting as a primary pathological factor. Future studies require direct assessment of CX-V activity in clinically relevant human models and patient tissues to determine its contribution to disease progression and examine its potential as a therapeutic target.<\/jats:p>","DOI":"10.3390\/brainsci16080890","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:05:19Z","timestamp":1787241919000},"page":"890","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial Complex V Dysfunction in Neurodegeneration: Secondary Bystander or Primary Driver?"],"prefix":"10.3390","volume":"16","author":[{"given":"Kate Erin","family":"Harris","sequence":"first","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, Royal Free Campus, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5936-1431","authenticated-orcid":false,"given":"Gerassimos","family":"Lascaratos","sequence":"additional","affiliation":[{"name":"King\u2019s College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK"},{"name":"Section of Ophthalmology, School of Life Course Sciences, King\u2019s College London, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5797-2922","authenticated-orcid":false,"given":"Kai-Yin","family":"Chau","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, Royal Free Campus, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BST20110773","article-title":"The ATP synthase: The understood, the uncertain and the unknown","volume":"41","author":"Walker","year":"2013","journal-title":"Biochem. 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