Sigma-1 receptor maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation at the mitochondria-associated membrane in amyotrophic lateral sclerosis

• DOI: 10.1016/j.nbd.2023.106031
• Publication Date: 2023-02-02T02:53:20Z
• Authors: Seiji Watanabe; Mai Horiuchi; Yuri Murata; Okiru Komine; Noe Kawade; Akira Sobue; Koji Yamanaka
• Keywords: Organelle; Fragmentation; Sigma-1 Receptor

Organelle contact sites are multifunctional platforms for maintaining cellular homeostasis. Alternations of the mitochondria-associated membranes (MAM), one organelle where endoplasmic reticulum (ER) is tethered to mitochondria, have been involved in pathogenesis neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, detailed mechanisms through which MAM integrity disrupted ALS not fully elucidated. Here, we examined whether AAA ATPase domain-containing protein 3A (ATAD3A), a mitochondrial membrane accumulating at MAM, ALS. We found that sigma-1 receptor (σ1R), an ER-resident causative inherited juvenile ALS, required ATAD3A maintain MAM. In addition, σ1R retained as monomer, associated with inhibition fragmentation. dimerization and fragmentation were significantly induced σ1R-deficient or SOD1-linked mouse spinal cords. Overall, these observations indicate induction by depends on maintains monomer inhibit Our findings suggest targeting σ1R–ATAD3A axis would be promising novel therapeutic strategy treat dysfunction neurological disorders,