Progressive Mitochondrial SOD1<sup>G93A</sup> Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral Sclerosis
In recent years, the “non-autonomous motor neuron death” hypothesis has become more consolidated behind amyotrophic lateral sclerosis (ALS). It postulates that cells other than motor neurons participate in the pathology. In fact, the involvement of the autonomic nervous system is fundamental since p...
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MDPI AG
2021-07-01
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| Series: | International Journal of Molecular Sciences |
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| author | Iago Méndez-López Francisco J. Sancho-Bielsa Tobias Engel Antonio G. García Juan Fernando Padín |
| author_facet | Iago Méndez-López Francisco J. Sancho-Bielsa Tobias Engel Antonio G. García Juan Fernando Padín |
| author_sort | Iago Méndez-López |
| collection | DOAJ |
| description | In recent years, the “non-autonomous motor neuron death” hypothesis has become more consolidated behind amyotrophic lateral sclerosis (ALS). 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 SOD1<sup>G93A</sup> mouse at pre-symptomatic and symptomatic stages. The mitochondrial accumulation of the mutated SOD1<sup>G93A</sup> 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 SOD1<sup>G93A</sup> 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. |
| first_indexed | 2024-03-10T09:13:53Z |
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| last_indexed | 2024-03-10T09:13:53Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-49ad1c58258b445c8c8762ad9fd6c7332023-11-22T05:44:39ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-012215819410.3390/ijms22158194Progressive Mitochondrial SOD1<sup>G93A</sup> Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral SclerosisIago Méndez-López0Francisco J. Sancho-Bielsa1Tobias Engel2Antonio G. García3Juan Fernando Padín4Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, SpainDepartamento de Ciencias Médicas, Facultad de Medicina, Universidad de Castilla-La Mancha (UCLM), 13005 Ciudad Real, SpainDepartment of Physiology & Medical Physics, RCSI University of Medicine and Health Sciences, D02 YN77 Dublin, IrelandInstituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, SpainInstituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, SpainIn recent years, the “non-autonomous motor neuron death” hypothesis has become more consolidated behind amyotrophic lateral sclerosis (ALS). 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 SOD1<sup>G93A</sup> mouse at pre-symptomatic and symptomatic stages. The mitochondrial accumulation of the mutated SOD1<sup>G93A</sup> 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 SOD1<sup>G93A</sup> 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.https://www.mdpi.com/1422-0067/22/15/8194amyotrophic lateral sclerosisSOD1<sup>G93A</sup>chromaffin cellmitochondrial dysfunctionOPA1 |
| spellingShingle | Iago Méndez-López Francisco J. Sancho-Bielsa Tobias Engel Antonio G. García Juan Fernando Padín Progressive Mitochondrial SOD1<sup>G93A</sup> Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral Sclerosis International Journal of Molecular Sciences amyotrophic lateral sclerosis SOD1<sup>G93A</sup> chromaffin cell mitochondrial dysfunction OPA1 |
| title | Progressive Mitochondrial SOD1<sup>G93A</sup> Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral Sclerosis |
| title_full | Progressive Mitochondrial SOD1<sup>G93A</sup> Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral Sclerosis |
| title_fullStr | Progressive Mitochondrial SOD1<sup>G93A</sup> Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral Sclerosis |
| title_full_unstemmed | Progressive Mitochondrial SOD1<sup>G93A</sup> Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral Sclerosis |
| title_short | Progressive Mitochondrial SOD1<sup>G93A</sup> Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral Sclerosis |
| title_sort | progressive mitochondrial sod1 sup g93a sup accumulation causes severe structural metabolic and functional aberrations through opa1 down regulation in a mouse model of amyotrophic lateral sclerosis |
| topic | amyotrophic lateral sclerosis SOD1<sup>G93A</sup> chromaffin cell mitochondrial dysfunction OPA1 |
| url | https://www.mdpi.com/1422-0067/22/15/8194 |
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