Journal
NEUROBIOLOGY OF DISEASE
Volume 179, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2023.106031
Keywords
mitochondoria-associated membrane; sigma-1 receptor; AAA ATPase domain-containing protein 3A; amyotrophic lateral sclerosis
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Organelle contact sites play a multifunctional role in maintaining cellular homeostasis. This study focuses on the mitochondria-associated membranes (MAM), a site where the endoplasmic reticulum (ER) is connected to the mitochondria, and its involvement in amyotrophic lateral sclerosis (ALS). The researchers found that a protein called ATAD3A, which accumulates at the MAM, is required for MAM maintenance and inhibits mitochondrial fragmentation. Targeting the interaction between sigma-1 receptor (a1R) and ATAD3A could be a promising therapeutic strategy for treating mitochondrial dysfunction in ALS.
Organelle contact sites are multifunctional platforms for maintaining cellular homeostasis. Alternations of the mitochondria-associated membranes (MAM), one of the organelle contact sites where the endoplasmic reticulum (ER) is tethered to the mitochondria, have been involved in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the detailed mechanisms through which MAM integrity is disrupted in ALS have not been fully elucidated. Here, we examined whether AAA ATPase domain-containing protein 3A (ATAD3A), a mitochondrial membrane AAA ATPase accumulating at the MAM, is involved in ALS. We found that sigma-1 receptor (a1R), an ER-resident MAM protein causative for inherited juvenile ALS, required ATAD3A to maintain the MAM. In addition, a1R retained ATAD3A as a monomer, which is associated with an inhibition of mitochondrial fragmentation. ATAD3A dimerization and mitochondrial fragmentation were significantly induced in a1R-deficient or SOD1-linked ALS mouse spinal cords. Overall, these observations indicate that MAM induction by a1R depends on ATAD3A and that a1R maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation. Our findings suggest that targeting a1R-ATAD3A axis would be promising for a novel therapeutic strategy to treat mitochondrial dysfunction in neurological disorders, including ALS.
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