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Biochim Biophys Acta. 2014 Aug;1842(8):1295-301. doi: 10.1016/j.bbadis.2014.02.009. Epub 2014 Feb 22.

Role of mitochondria in mutant SOD1 linked amyotrophic lateral sclerosis.

Author information

1
Frances and Joseph Weinberg Unit for ALS Research, Farber Institute for the Neurosciences, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA.
2
Frances and Joseph Weinberg Unit for ALS Research, Farber Institute for the Neurosciences, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: davide.trotti@jefferson.edu.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an adult onset characterized by loss of both upper and lower motor neurons. In ~10% of cases, patients developed ALS with an apparent genetic linkage (familial ALS or fALS). Approximately 20% of fALS displays mutations in the SOD1 gene encoding superoxide dismutase 1. There are many proposed cellular and molecular mechanisms among which, mitochondrial dysfunctions occur early, prior to symptoms occurrence. In this review, we modeled the effect of mutant SOD1 protein via the formation of a toxic complex with Bcl2 on mitochondrial bioenergetics. Furthermore, we discuss that the shutdown of ATP permeation through mitochondrial outer membrane could lead to both respiration inhibition and temporary mitochondrial hyperpolarization. Moreover, we reviewed mitochondrial calcium signaling, oxidative stress, fission and fusion, autophagy and apoptosis in mutant SOD1-linked ALS. Functional defects in mitochondria appear early before symptoms are manifested in ALS. Therefore, mitochondrial dysfunction is a promising therapeutic target in ALS.

KEYWORDS:

Amyotrophic lateral sclerosis; Mitochondria; Oxidative stress

PMID:
24568860
PMCID:
PMC4074562
DOI:
10.1016/j.bbadis.2014.02.009
[Indexed for MEDLINE]
Free PMC Article

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