Sakakibara Kaori, Eiyama Akinori, Suzuki Sho W, Sakoh-Nakatogawa Machiko, Okumura Nobuaki, Tani Motohiro, Hashimoto Ayako, Nagumo Sachiyo, Kondo-Okamoto Noriko, Kondo-Kakuta Chika, Asai Eri, Kirisako Hiromi, Nakatogawa Hitoshi, Kuge Osamu, Takao Toshifumi, Ohsumi Yoshinori, Okamoto Koji
Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan Frontier Research Center, Tokyo Institute of Technology, Kanagawa, Japan.
EMBO J. 2015 Nov 3;34(21):2703-19. doi: 10.15252/embj.201591440. Epub 2015 Oct 5.
Degradation of mitochondria via selective autophagy, termed mitophagy, contributes to mitochondrial quality and quantity control whose defects have been implicated in oxidative phosphorylation deficiency, aberrant cell differentiation, and neurodegeneration. How mitophagy is regulated in response to cellular physiology remains obscure. Here, we show that mitophagy in yeast is linked to the phospholipid biosynthesis pathway for conversion of phosphatidylethanolamine to phosphatidylcholine by the two methyltransferases Cho2 and Opi3. Under mitophagy-inducing conditions, cells lacking Opi3 exhibit retardation of Cho2 repression that causes an anomalous increase in glutathione levels, leading to suppression of Atg32, a mitochondria-anchored protein essential for mitophagy. In addition, loss of Opi3 results in accumulation of phosphatidylmonomethylethanolamine (PMME) and, surprisingly, generation of Atg8-PMME, a mitophagy-incompetent lipid conjugate of the autophagy-related ubiquitin-like modifier. Amelioration of Atg32 expression and attenuation of Atg8-PMME conjugation markedly rescue mitophagy in opi3-null cells. We propose that proper regulation of phospholipid methylation is crucial for Atg32-mediated mitophagy.
通过选择性自噬降解线粒体，即线粒体自噬，有助于线粒体质量和数量的控制，其缺陷与氧化磷酸化缺陷、异常细胞分化和神经退行性变有关。线粒体自噬如何响应细胞生理过程进行调控仍不清楚。在此，我们表明酵母中的线粒体自噬与磷脂生物合成途径相关，该途径通过两种甲基转移酶Cho2和Opi3将磷脂酰乙醇胺转化为磷脂酰胆碱。在诱导线粒体自噬的条件下，缺乏Opi3的细胞表现出Cho2抑制作用的延迟，这导致谷胱甘肽水平异常升高，从而抑制Atg32，Atg32是线粒体自噬所必需的一种锚定在线粒体上的蛋白质。此外，Opi3的缺失导致磷脂酰单甲基乙醇胺（PMME）的积累，令人惊讶的是，还会产生Atg8-PMME，这是一种与自噬相关的泛素样修饰因子的无线粒体自噬能力的脂质共轭物。Atg32表达的改善和Atg8-PMME共轭作用的减弱显著挽救了opi3缺失细胞中的线粒体自噬。我们提出，磷脂甲基化的适当调控对于Atg32介导的线粒体自噬至关重要。
