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Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. Despite the increasing effort in understanding the etiopathology of ALS, it still remains an obscure disease, and no therapies are currently available to h...

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Autores principales: Candelise, Niccolò, Salvatori, Illari, Scaricamazza, Silvia, Nesci, Valentina, Zenuni, Henri, Ferri, Alberto, Valle, Cristiana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8951432/
https://www.ncbi.nlm.nih.gov/pubmed/35323676
http://dx.doi.org/10.3390/metabo12030233
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author Candelise, Niccolò
Salvatori, Illari
Scaricamazza, Silvia
Nesci, Valentina
Zenuni, Henri
Ferri, Alberto
Valle, Cristiana
author_facet Candelise, Niccolò
Salvatori, Illari
Scaricamazza, Silvia
Nesci, Valentina
Zenuni, Henri
Ferri, Alberto
Valle, Cristiana
author_sort Candelise, Niccolò
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. 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–Zn 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 “metabolic threshold”, which may appear pivotal in ALS pathogenesis.
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spelling pubmed-89514322022-03-26 Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship Candelise, Niccolò Salvatori, Illari Scaricamazza, Silvia Nesci, Valentina Zenuni, Henri Ferri, Alberto Valle, Cristiana Metabolites Review Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. 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–Zn 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 “metabolic threshold”, which may appear pivotal in ALS pathogenesis. MDPI 2022-03-09 /pmc/articles/PMC8951432/ /pubmed/35323676 http://dx.doi.org/10.3390/metabo12030233 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Candelise, Niccolò
Salvatori, Illari
Scaricamazza, Silvia
Nesci, Valentina
Zenuni, Henri
Ferri, Alberto
Valle, Cristiana
Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship
title Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship
title_full Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship
title_fullStr Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship
title_full_unstemmed Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship
title_short Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship
title_sort mechanistic insights of mitochondrial dysfunction in amyotrophic lateral sclerosis: an update on a lasting relationship
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8951432/
https://www.ncbi.nlm.nih.gov/pubmed/35323676
http://dx.doi.org/10.3390/metabo12030233
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