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Review
. 2023 Oct 24;14(11):1981.
doi: 10.3390/genes14111981.

Mitochondria, a Key Target in Amyotrophic Lateral Sclerosis Pathogenesis

Emmanuelle C Genin  1 , Mélanie Abou-Ali  1 , Véronique Paquis-Flucklinger  1
Affiliations
Review

Mitochondria, a Key Target in Amyotrophic Lateral Sclerosis Pathogenesis

Emmanuelle C Genin et al. Genes (Basel). .

Abstract

Mitochondrial dysfunction occurs in numerous neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS), where it contributes to motor neuron (MN) death. Of all the factors involved in ALS, mitochondria have been considered as a major player, as secondary mitochondrial dysfunction has been found in various models and patients. Abnormal mitochondrial morphology, defects in mitochondrial dynamics, altered activities of respiratory chain enzymes and increased production of reactive oxygen species have been described. Moreover, the identification of CHCHD10 variants in ALS patients was the first genetic evidence that a mitochondrial defect may be a primary cause of MN damage and directly links mitochondrial dysfunction to the pathogenesis of ALS. In this review, we focus on the role of mitochondria in ALS and highlight the pathogenic variants of ALS genes associated with impaired mitochondrial functions. The multiple pathways demonstrated in ALS pathogenesis suggest that all converge to a common endpoint leading to MN loss. This may explain the disappointing results obtained with treatments targeting a single pathological process. Fighting against mitochondrial dysfunction appears to be a promising avenue for developing combined therapies in the future.

Keywords: ALS genes; CHCHD10; amyotrophic lateral sclerosis; frontotemporal dementia; mitochondria; motor neuron disease.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic illustration of mitochondrial dysfunctions in ALS pathogenesis (created with biorender.com, accessed on 29 September 2023). Abnormal mitochondrial morphology, increased ROS production, defects in mitochondrial dynamics, impaired axonal transport, disruption of axonal transport and disruption of MAM integrity have been described both in ALS patients and in ALS models. ALS: amyotrophic lateral sclerosis; MAM: mitochondrial-associated membranes; ROS: reactive oxygen species.
Figure 2
Figure 2
Schematic illustration of different mitochondrial functions impacted by ALS variants (created with biorender.com, accessed on 29 September 2023). Several mechanisms leading to mitochondrial dysfunctions, such as protein aggregation, OXPHOS, oxidative stress, Ca2+ homeostasis, mitochondrial morphology, mitophagy and axonal transport, have been described in ALS. In motor neurons, mitochondrial dysfunction leads to decreased mitochondrial membrane potential, decreased OXPHOS and impaired mitochondrial import. In CHCHD10-related ALS, SLP2/PHB aggregates and PHB complex instability are key factors which trigger the OMA1/OPA1 cascade leading to the imbalance in S-OPA1/L-OPA1 forms, abnormal mitochondrial dynamics and apoptosis. PHB instability and disrupted OPA1-mitofilin interaction should lead to instability of MICOS complex. CHCHD10 is also a partner of MICOS, and in ALS it participates in MICOS complex disassembly, loss of cristae structure and OXPHOS defects. MAMs: mitochondrial-associated membranes; MICOS: mitochondrial contact site and cristae organizing system; RC: respiratory chain; IMMT: mitofilin; S-OPA1: short form of OPA1; L-OPA1: long form of OPA1; ΔФ: mitochondrial membrane potential; PHB: prohibitin complex.
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References

    1. Van Es M.A., Hardiman O., Chio A., Al-Chalabi A., Pasterkamp R.J., Veldink J.H., Van Den Berg L.H. Amyotrophic Lateral Sclerosis. Lancet. 2017;390:2084–2098. doi: 10.1016/S0140-6736(17)31287-4. - DOI - PubMed
    1. Hardiman O., Al-Chalabi A., Chio A., Corr E.M., Logroscino G., Robberecht W., Shaw P.J., Simmons Z., Van Den Berg L.H. Amyotrophic Lateral Sclerosis. Nat. Rev. Dis. Primers. 2017;3:17071. doi: 10.1038/nrdp.2017.71. - DOI - PubMed
    1. Prasad A., Bharathi V., Sivalingam V., Girdhar A., Patel B.K. Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis. Front. Mol. Neurosci. 2019;12:25. doi: 10.3389/fnmol.2019.00025. - DOI - PMC - PubMed
    1. Xu L., Liu T., Liu L., Yao X., Chen L., Fan D., Zhan S., Wang S. Global Variation in Prevalence and Incidence of Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis. J. Neurol. 2020;267:944–953. doi: 10.1007/s00415-019-09652-y. - DOI - PubMed
    1. Marin B., Boumédiene F., Logroscino G., Couratier P., Babron M.-C., Leutenegger A.L., Copetti M., Preux P.-M., Beghi E. Variation in Worldwide Incidence of Amyotrophic Lateral Sclerosis: A Meta-Analysis. Int. J. Epidemiol. 2016;46:dyw061. doi: 10.1093/ije/dyw061. - DOI - PMC - PubMed

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