Sigma-1 receptor maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation at the mitochondria-associated membrane in amyotrophic lateral sclerosis
Sigma-1 receptor maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation at the mitochondria-associated membrane in amyotrophic lateral sclerosis
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DOI：
10.1016/j.nbd.2023.106031
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发表时间：
2023-02-10
影响因子：
6.1
通讯作者：
Yamanaka，Koji
中科院分区：
文献类型：
--
作者：
Watanabe，Seiji;Horiuchi，Mai;Yamanaka，Koji
细胞器接触部位是维持细胞内稳态的多功能平台。线粒体相关膜（MAM）是内质网（ER）与线粒体相连接的细胞器接触部位之一，其改变参与了包括肌萎缩侧索硬化（ALS）在内的神经退行性疾病的发病机制。然而，MAM完整性在ALS中被破坏的详细机制尚未完全阐明。在这里，我们研究了是否AAA ATP酶结构域包含蛋白3A（ATAD 3A），线粒体膜AAA ATP酶积累在MAM，参与ALS。我们发现sigma-1受体（σ 1 R），一种引起遗传性幼年型ALS的ER驻留MAM蛋白，需要ATAD 3A来维持MAM。此外，σ 1 R保留ATAD 3A作为单体，这与抑制线粒体片段化有关。ATAD 3A二聚化和线粒体片段化在σ 1 R缺陷或SOD 1连锁的ALS小鼠脊髓中显著诱导。总之，这些观察结果表明，σ 1 R诱导MAM依赖于ATAD 3A，σ 1 R维持ATAD 3A作为单体以抑制线粒体片段化。我们的研究结果表明，靶向σ 1 R-ATAD 3A轴将有望成为治疗神经系统疾病（包括ALS）中线粒体功能障碍的新治疗策略。
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 (σ1R), an ER-resident MAM protein causative for inherited juvenile ALS, required ATAD3A to maintain the MAM. In addition, σ1R retained ATAD3A as a monomer, which is associated with an inhibition of mitochondrial fragmentation. ATAD3A dimerization and mitochondrial fragmentation were significantly induced in σ1R-deficient or SOD1-linked ALS mouse spinal cords. Overall, these observations indicate that MAM induction by σ1R depends on ATAD3A and that σ1R maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation. Our findings suggest that targeting σ1R–ATAD3A axis would be promising for a novel therapeutic strategy to treat mitochondrial dysfunction in neurological disorders, including ALS.