Methyl pyruvate rescues mitochondrial damage caused by SIGMAR1 mutation related to amyotrophic lateral sclerosis

• Published in: Biochimica et biophysica acta Vol. 1840; no. 12; pp. 3320 - 3334
• Main Authors: Tagashira, Hideaki, Shinoda, Yasuharu, Shioda, Norifumi, Fukunaga, Kohji
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2014
• Subjects: adenosine triphosphate; Amyotrophic lateral sclerosis; Autophagy; calcium; cell membranes; dissociation; DNA-binding proteins; endoplasmic reticulum; Endoplasmic reticulum stress; gene overexpression; genes; inclusion bodies; mitochondria; motor neurons; mutation; Neurodegeneration; proteasome endopeptidase complex; pyruvic acid; Sigma-1 receptor; ubiquitination; PBS; IP3R; TCA cycle; FTLD; ALS; Amyotrophic lateral sclerosis; σ1R; PERK; ER; GRP75; IP3; Sigma-1 receptor; Autophagy; Endoplasmic reticulum stress; DMEM; Neurodegeneration; FBS; MAM; VDAC; Mfn2; TMs; ATP
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2014.08.012

Amyotrophic lateral sclerosis (ALS) is a disease caused by motor neuron degeneration. Recently, a novel SIGMAR1 gene variant (p.E102Q) was discovered in some familial ALS patients. We address mechanisms underlying neurodegeneration caused by the mutation using Neuro2A cells overexpressing σ1RE102Q, a protein of a SIGMAR1 gene variant (p.E102Q) and evaluate potential amelioration by ATP production via methyl pyruvate (MP) treatment. σ1RE102Q overexpression promoted dissociation of the protein from the endoplasmic reticulum (ER) membrane and cytoplasmic aggregation, which in turn impaired mitochondrial ATP production and proteasome activity. Under ER stress conditions, overexpression of wild-type σ1R suppressed ER stress-induced mitochondrial injury, whereas σ1RE102Q overexpression aggravated mitochondrial damage and induced autophagic cell death. Moreover, σ1RE102Q-overexpressing cells showed aberrant extra-nuclear localization of the TAR DNA-binding protein (TDP-43), a condition exacerbated by ER stress. Treatment of cells with the mitochondrial Ca2+ transporter inhibitor Ru360 mimicked the effects of σ1RE102Q overexpression, indicating that aberrant σ1R-mediated mitochondrial Ca2+ transport likely underlies TDP-43 extra-nuclear localization, segregation in inclusion bodies, and ubiquitination. Finally, enhanced ATP production promoted by methyl pyruvate (MP) treatment rescued proteasome impairment and TDP-43 extra-nuclear localization caused by σ1RE102Q overexpression. Our observations suggest that neurodegeneration seen in some forms of ALS are due in part to aberrant mitochondrial ATP production and proteasome activity as well as TDP-43 mislocalization resulting from the SIGMAR1 mutation. ATP supplementation by MP represents a potential therapeutic strategy to treat ALS caused by SIGMAR1 mutation. [Display omitted] •ALS-related σ1RE102Q mutation promotes its dissociation from the endoplasmic reticulum (ER) membrane.•The σ1RE102Q overexpression impairs mitochondrial ATP production and induced neuronal cell death.•The mitochondrial ATP reduction aggravates mislocalization and ubiquitination of TDP-43.•ATP supplementation with methyl pyruvate rescues TDP-43 mislocalization and neuronal cell death caused by σ1RE102Q.