Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
J Biol Chem. 2020 May 8;295(19):6543-6560. doi: 10.1074/jbc.RA119.010983. Epub 2020 Apr 3.
Optic atrophy 1 (OPA1) is a dynamin protein that mediates mitochondrial fusion at the inner membrane. OPA1 is also necessary for maintaining the cristae and thus essential for supporting cellular energetics. OPA1 exists as membrane-anchored long form (L-OPA1) and short form (S-OPA1) that lacks the transmembrane region and is generated by cleavage of L-OPA1. Mitochondrial dysfunction and cellular stresses activate the inner membrane-associated zinc metallopeptidase OMA1 that cleaves L-OPA1, causing S-OPA1 accumulation. The prevailing notion has been that L-OPA1 is the functional form, whereas S-OPA1 is an inactive cleavage product in mammals, and that stress-induced OPA1 cleavage causes mitochondrial fragmentation and sensitizes cells to death. However, S-OPA1 contains all functional domains of dynamin proteins, suggesting that it has a physiological role. Indeed, we recently demonstrated that S-OPA1 can maintain cristae and energetics through its GTPase activity, despite lacking fusion activity. Here, applying oxidant insult that induces OPA1 cleavage, we show that cells unable to generate S-OPA1 are more sensitive to this stress under obligatory respiratory conditions, leading to necrotic death. These findings indicate that L-OPA1 and S-OPA1 differ in maintaining mitochondrial function. Mechanistically, we found that cells that exclusively express L-OPA1 generate more superoxide and are more sensitive to Ca-induced mitochondrial permeability transition, suggesting that S-OPA1, and not L-OPA1, protects against cellular stress. Importantly, silencing of OMA1 expression increased oxidant-induced cell death, indicating that stress-induced OPA1 cleavage supports cell survival. Our findings suggest that S-OPA1 generation by OPA1 cleavage is a survival mechanism in stressed cells.
视神经萎缩 1（OPA1）是一种动力蛋白蛋白，在内膜处介导线粒体融合。OPA1 对于维持嵴也是必需的，因此对于支持细胞能量至关重要。OPA1 存在膜锚定的长形式（L-OPA1）和短形式（S-OPA1），后者缺乏跨膜区，是由 L-OPA1 的切割产生的。线粒体功能障碍和细胞应激激活内膜相关锌金属肽酶 OMA1，其切割 L-OPA1，导致 S-OPA1 积累。普遍的观点是 L-OPA1 是功能形式，而 S-OPA1 是哺乳动物中无活性的切割产物，应激诱导的 OPA1 切割导致线粒体碎片化并使细胞对死亡敏感。然而，S-OPA1 包含动力蛋白蛋白的所有功能域，表明它具有生理作用。事实上，我们最近证明，尽管缺乏融合活性，S-OPA1 可以通过其 GTPase 活性维持嵴和能量。在这里，我们应用诱导 OPA1 切割的氧化剂损伤，表明在必需呼吸条件下，无法产生 S-OPA1 的细胞对这种应激更为敏感，导致坏死性死亡。这些发现表明 L-OPA1 和 S-OPA1 在维持线粒体功能方面存在差异。从机制上讲，我们发现仅表达 L-OPA1 的细胞会产生更多的超氧化物，并且对 Ca 诱导的线粒体通透性转换更为敏感，这表明 S-OPA1 而不是 L-OPA1 可以保护细胞免受应激。重要的是，沉默 OMA1 表达增加了氧化剂诱导的细胞死亡，表明应激诱导的 OPA1 切割支持细胞存活。我们的研究结果表明，OPA1 切割产生的 S-OPA1 是应激细胞的一种生存机制。
