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It postulates that cells other than motor neurons participate in the pathology. In fact, the involvement of the autonomic nervous system is fundamental since patients die of sudden death when they become unable to compensate for cardiorespiratory arrest. Mitochondria are thought to play a fundamental role in the physiopathology of ALS, as they are compromised in multiple ALS models in different cell types, and it also occurs in other neurodegenerative diseases. Our study aimed to uncover mitochondrial alterations in the sympathoadrenal system of a mouse model of ALS, from a structural, bioenergetic and functional perspective during disease instauration. We studied the adrenal chromaffin cell from mutant SOD1G93A mouse at pre-symptomatic and symptomatic stages. The mitochondrial accumulation of the mutated SOD1G93A protein and the down-regulation of optic atrophy protein-1 (OPA1) provoke mitochondrial ultrastructure alterations prior to the onset of clinical symptoms. These changes affect mitochondrial fusion dynamics, triggering mitochondrial maturation impairment and cristae swelling, with increased size of cristae junctions. The functional consequences are a loss of mitochondrial membrane potential and changes in the bioenergetics profile, with reduced maximal respiration and spare respiratory capacity of mitochondria, as well as enhanced production of reactive oxygen species. This study identifies mitochondrial dynamics regulator OPA1 as an interesting therapeutic target in ALS. Additionally, our findings in the adrenal medulla gland from presymptomatic stages highlight the relevance of sympathetic impairment in this disease. Specifically, we show new SOD1G93A toxicity pathways affecting cellular energy metabolism in non-motor neurons, which offer a possible link between cell specific metabolic phenotype and the progression of ALS.<\/jats:p>","DOI":"10.3390\/ijms22158194","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T12:59:24Z","timestamp":1627649964000},"page":"8194","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Progressive Mitochondrial SOD1G93A Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral Sclerosis"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3428-1109","authenticated-orcid":false,"given":"Iago","family":"M\u00e9ndez-L\u00f3pez","sequence":"first","affiliation":[{"name":"Instituto Te\u00f3filo Hernando and Departamento de Farmacolog\u00eda y Terap\u00e9utica, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid (UAM), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3521-5477","authenticated-orcid":false,"given":"Francisco J.","family":"Sancho-Bielsa","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias M\u00e9dicas, Facultad de Medicina, Universidad de Castilla-La Mancha (UCLM), 13005 Ciudad Real, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9137-0637","authenticated-orcid":false,"given":"Tobias","family":"Engel","sequence":"additional","affiliation":[{"name":"Department of Physiology & Medical Physics, RCSI University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland"},{"name":"FutureNeuro SFI Research Centre for Chronic and Rare Neurological Diseases, RCSI University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio G.","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Instituto Te\u00f3filo Hernando and Departamento de Farmacolog\u00eda y Terap\u00e9utica, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid (UAM), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Fernando","family":"Pad\u00edn","sequence":"additional","affiliation":[{"name":"Instituto Te\u00f3filo Hernando and Departamento de Farmacolog\u00eda y Terap\u00e9utica, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid (UAM), 28029 Madrid, Spain"},{"name":"Departamento de Ciencias M\u00e9dicas, Facultad de Medicina, Universidad de Castilla-La Mancha (UCLM), 13005 Ciudad Real, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,30]]},"reference":[{"key":"ref_1","first-page":"744","article-title":"Deux cas d\u2019atrophie musculaire progressive avec lesions de la substance grise et des faisceaux anterolateraux de la moelle epiniere","volume":"2","author":"Charcot","year":"1869","journal-title":"Arch. 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