Details

Autor(en) / Beteiligte

• 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

Titel

Phospholipid methylation controls Atg32-mediated mitophagy and Atg8 recycling

Ist Teil von

• The EMBO journal, 2015-11, Vol.34 (21), p.2703-2719

Ort / Verlag

England: Blackwell Publishing Ltd

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• 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. Synopsis The phosphatidylethanolamine (PE) methyltransferase Cho2 is repressed in yeast under non‐fermentable conditions, causing a decrease in the glutathione (GSH) levels and subsequent induction of the mitophagy protein Atg32. Loss of phospholipid methyltransferase Opi3 delays Cho2 repression. Prolonged Cho2 expression causes accumulation of its product phosphatidylmonomethylethanolamine (PMME) and increases the GSH levels, leading to suppression of Atg32 induction and disruption of mitophagy. Atg8, known to be PE‐linked during autophagosome formation, is aberrantly conjugated to PMME in opi3‐null cells. Atg8–PMME cannot be efficiently delipidated by the cysteine protease Atg4, thereby attenuating Atg8 recycling and thus mitophagy. The phosphatidylethanolamine (PE) methyltransferase Cho2 is repressed in yeast under non‐fermentable conditions, causing a decrease in the glutathione (GSH) levels and subsequent induction of the mitophagy protein Atg32.