{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T07:24:55Z","timestamp":1794468295363,"version":"4.9.1"},"reference-count":343,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a devastating and invariably fatal disease for which currently available disease-modifying therapies provide only modest benefit. Defining its underlying pathogenesis is therefore essential for the development of effective treatments. Increasing evidence indicates that ALS is not restricted to motor neurons but involves multiple neuronal and glial systems, extending to peripheral organs, often at subclinical levels. These multisystem alterations may precede overt neurological symptoms by years and are accompanied by metabolic disturbances, including progressive weight loss and hypermetabolism. In peripheral tissues, ongoing cellular turnover and associated immune and inflammatory responses may further increase energy demand. Within this framework, mitochondrial dysfunction emerges as a central mechanism underlying impaired bioenergetics and systemic metabolic failure. Mitochondria not only regulate energy production but also contribute to oxidative stress, which in turn exacerbates mitochondrial injury, creating a self-amplifying cycle. Importantly, many genetic forms of familial ALS directly affect mitochondrial pathways, and similar biochemical abnormalities are observed in sporadic ALS. These shared features suggest that mitochondrial dysfunction represents a common pathway across ALS subtypes. Targeting upstream mechanisms of mitochondrial impairment may therefore provide a unifying strategy for understanding ALS pathogenesis and developing effective therapies.<\/jats:p>","DOI":"10.3390\/biom16081126","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T01:43:27Z","timestamp":1785721407000},"page":"1126","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["ALS: An Organism-Wide Bioenergetic Failure Due to Mitochondrial Dysfunctions?"],"prefix":"10.3390","volume":"16","author":[{"given":"Hiroshi","family":"Mitsumoto","sequence":"first","affiliation":[{"name":"Department of Neurology, Neurological Institute of New York, Columbia University, 710 West 168 St., New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Blasco","sequence":"additional","affiliation":[{"name":"Laboratoire de Biochimie et Biologie Mol\u00e9culaire, H\u00f4pital Bretonneau, CHU de Tours 2, Bd Tonnell\u00e9, 37044 Tours, France"},{"name":"Universit\u00e9 de Tours, INSERM, Imaging Brain & Neuropsychiatry iBraiN U1253, 37032 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1625-8845","authenticated-orcid":false,"given":"Philippe","family":"Corcia","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Tours, INSERM, Imaging Brain & Neuropsychiatry iBraiN U1253, 37032 Tours, France"},{"name":"Centre de Reference Coordinateur SLA et Autres Maladies du Motoneurone, CHU Bretonneau 2 Boulevard TONNELLE, 37044 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7698-3854","authenticated-orcid":false,"given":"Vincenzo","family":"Silani","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, 20149 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, \u201cDino Ferrari\u201d Center, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"ref_1","unstructured":"Mitsumoto, H., Chad, C.A., and Pioro, E.P. 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