高通量筛选可识别 OPA1 成纤维细胞中线粒体片段化的抑制因子

High-throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts

Keywords：genetic modifiers; high-throughput screening; mitochondrial dynamics; OPA1; phospholipid metabolism

关键词：基因修饰剂；高通量筛选；线粒体动力学; OPA1;磷脂代谢
作者：Cretin Emma, Lopes Priscilla, Vimont Elodie, Tatsuta Takashi, Langer Thomas, Gazi Anastasia, Sachse Martin, Yu-Wai-Man Patrick, Reynier Pascal, Wai Timothy
出版期刊：《EMBO Molecular Medicine》 2021/5/20

Abstract：

Mutations in OPA1 cause autosomal dominant optic atrophy (DOA) as well as DOA+, a phenotype characterized by more severe neurological deficits. OPA1 deficiency causes mitochondrial fragmentation and also disrupts cristae, respiration, mitochondrial DNA (mtDNA) maintenance, and cell viability. It has not yet been established whether phenotypic severity can be modulated by genetic modifiers of OPA1. We screened the entire known mitochondrial proteome (1,531 genes) to identify genes that control mitochondrial morphology using a first‐in‐kind imaging pipeline. We identified 145 known and novel candidate genes whose depletion promoted elongation or fragmentation of the mitochondrial network in control fibroblasts and 91 in DOA+ patient fibroblasts that prevented mitochondrial fragmentation, including phosphatidyl glycerophosphate synthase (PGS1). PGS1 depletion reduces CL content in mitochondria and rebalances mitochondrial dynamics in OPA1‐deficient fibroblasts by inhibiting mitochondrial fission, which improves defective respiration, but does not rescue mtDNA depletion, cristae dysmorphology, or apoptotic sensitivity. Our data reveal that the multifaceted roles of OPA1 in mitochondria can be functionally uncoupled by modulating mitochondrial lipid metabolism, providing novel insights into the cellular relevance of mitochondrial fragmentation.

文章摘要：

OPA1 突变导致常染色体显性视神经萎缩 (DOA) 以及 DOA+，这是一种以更严重的神经功能缺损为特征的表型。 OPA1 缺乏会导致线粒体断裂，还会破坏嵴、呼吸、线粒体 DNA (mtDNA) 维持和细胞活力。尚未确定是否可以通过 OPA1 的遗传修饰剂调节表型严重性。我们使用首创的成像管道筛选了整个已知的线粒体蛋白质组（1,531 个基因），以识别控制线粒体形态的基因。我们鉴定了 145 个已知和新的候选基因，它们的缺失促进了对照成纤维细胞中线粒体网络的伸长或断裂，以及 91 个 DOA+ 患者成纤维细胞阻止了线粒体断裂，包括磷脂酰甘油磷酸合酶 (PGS1)。 PGS1 耗竭通过抑制线粒体分裂减少线粒体中的 CL 含量并重新平衡 OPA1 缺陷成纤维细胞的线粒体动力学，从而改善呼吸功能障碍，但不能挽救 mtDNA 耗竭、嵴畸形或凋亡敏感性。我们的数据表明，OPA1 在线粒体中的多方面作用可以通过调节线粒体脂质代谢在功能上解耦，从而为线粒体片段化的细胞相关性提供新的见解。

点击链接即可查看和下载文章：https://www.embopress.org/doi/full/10.15252/emmm.202013579

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