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Despite the increasing effort in understanding the etiopathology of ALS, it still remains an obscure disease, and no therapies are currently available to halt its progression. Following the discovery of the first gene associated with familial forms of ALS, Cu\u2013Zn superoxide dismutase, it appeared evident that mitochondria were key elements in the onset of the pathology. However, as more and more ALS-related genes were discovered, the attention shifted from mitochondria impairment to other biological functions such as protein aggregation and RNA metabolism. In recent years, mitochondria have again earned central, mechanistic roles in the pathology, due to accumulating evidence of their derangement in ALS animal models and patients, often resulting in the dysregulation of the energetic metabolism. In this review, we first provide an update of the last lustrum on the molecular mechanisms by which the most well-known ALS-related proteins affect mitochondrial functions and cellular bioenergetics. Next, we focus on evidence gathered from human specimens and advance the concept of a cellular-specific mitochondrial \u201cmetabolic threshold\u201d, which may appear pivotal in ALS pathogenesis.<\/jats:p>","DOI":"10.3390\/metabo12030233","type":"journal-article","created":{"date-parts":[[2022,3,9]],"date-time":"2022-03-09T11:30:38Z","timestamp":1646825438000},"page":"233","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship"],"prefix":"10.3390","volume":"12","author":[{"given":"Niccol\u00f2","family":"Candelise","sequence":"first","affiliation":[{"name":"IRCCS Fondazione Santa Lucia, 00179 Rome, Italy"},{"name":"Institute of Translational Pharmacology (IFT), Consiglio Nazionale delle Ricerche (CNR), 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Illari","family":"Salvatori","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Santa Lucia, 00179 Rome, Italy"},{"name":"Department of Experimental Medicine, Faculty of Medicine, University of Roma \u201cLa Sapienza\u201d, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Scaricamazza","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Santa Lucia, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Nesci","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Santa Lucia, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1695-1359","authenticated-orcid":false,"given":"Henri","family":"Zenuni","sequence":"additional","affiliation":[{"name":"Unit of Neurology, Department of Systems Medicine, University of Roma Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4097-0605","authenticated-orcid":false,"given":"Alberto","family":"Ferri","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Santa Lucia, 00179 Rome, Italy"},{"name":"Institute of Translational Pharmacology (IFT), Consiglio Nazionale delle Ricerche (CNR), 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0914-6511","authenticated-orcid":false,"given":"Cristiana","family":"Valle","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Santa Lucia, 00179 Rome, Italy"},{"name":"Institute of Translational Pharmacology (IFT), Consiglio Nazionale delle Ricerche (CNR), 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1016\/S0140-6736(17)31287-4","article-title":"Amyotrophic lateral sclerosis","volume":"390","author":"Hardiman","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17085","DOI":"10.1038\/nrdp.2017.85","article-title":"Amyotrophic lateral sclerosis","volume":"3","author":"Hardiman","year":"2017","journal-title":"Nat. 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