Phospholipid methylation controls Atg32-mediated mitophagy and Atg8 recycling
Phospholipid methylation controls Atg32-mediated mitophagy and Atg8 recycling
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DOI：
10.15252/embj.201591440
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发表时间：
2015-11-03
期刊：
影响因子：
11.4
通讯作者：
Okamoto, Koji
中科院分区：
文献类型：
--
作者：
Sakakibara, Kaori;Eiyama, Akinori;Okamoto, Koji
通过选择性自噬（称为线粒体自噬）降解线粒体有助于线粒体质量和数量控制，其缺陷与氧化磷酸化缺陷、异常细胞分化和神经变性有关。线粒体自噬如何响应细胞生理学进行调节仍然不清楚。在这里，我们发现酵母中的线粒体自噬与磷脂生物合成途径有关，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。在线粒体自噬诱导条件下，缺乏 Opi3 的细胞表现出 Cho2 抑制的延迟，导致谷胱甘肽水平异常增加，从而抑制 Atg32（一种线粒体自噬所必需的线粒体锚定蛋白）。此外，Opi3 的缺失会导致磷脂酰单甲基乙醇胺 (PMME) 的积累，并且令人惊讶的是，会产生 Atg8-PMME，这是一种自噬相关泛素样修饰剂的无线粒体自噬能力的脂质缀合物。 Atg32 表达的改善和 Atg8-PMME 缀合的减弱可显着挽救 opi3 缺失细胞中的线粒体自噬。我们认为磷脂甲基化的适当调节对于 Atg32 介导的线粒体自噬至关重要。
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.