title: Phospholipid methylation controls Atg32-mediated mitophagy and Atg8 recycling.
abstract: 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.
authors.affiliation: Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakakibara
authors.affiliation: Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Eiyama
authors.affiliation: Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan Frontier Research Center, Tokyo Institute of Technology, Kanagawa, Japan.
authors.forename: Sho W
authors.initials: SW
authors.lastname: Suzuki
authors.affiliation: Frontier Research Center, Tokyo Institute of Technology, Kanagawa, Japan.
authors.forename: Machiko
authors.initials: M
authors.lastname: Sakoh-Nakatogawa
authors.affiliation: Institute for Protein Research, Osaka University, Osaka, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Okumura
authors.affiliation: Department of Chemistry, Kyushu University, Fukuoka, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Tani
authors.affiliation: Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Hashimoto
authors.affiliation: Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Nagumo
authors.affiliation: Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Kondo-Okamoto
authors.affiliation: Frontier Research Center, Tokyo Institute of Technology, Kanagawa, Japan.
authors.forename: Chika
authors.initials: C
authors.lastname: Kondo-Kakuta
authors.affiliation: Frontier Research Center, Tokyo Institute of Technology, Kanagawa, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Asai
authors.affiliation: Frontier Research Center, Tokyo Institute of Technology, Kanagawa, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kirisako
authors.affiliation: Frontier Research Center, Tokyo Institute of Technology, Kanagawa, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakatogawa
authors.affiliation: Department of Chemistry, Kyushu University, Fukuoka, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kuge
authors.affiliation: Institute for Protein Research, Osaka University, Osaka, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takao
authors.affiliation: Frontier Research Center, Tokyo Institute of Technology, Kanagawa, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ohsumi
authors.affiliation: Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan kokamoto@fbs.osaka-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Okamoto
mesh_terms: D000071190:Autophagy-Related Protein 8 Family; D000071183:Autophagy-Related Proteins; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D008745:Methylation; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D063306:Mitophagy; D010743:Phospholipids / Q000378:metabolism*; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism* / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: C113757:ATG8 protein, S cerevisiae; C543183:Atg32 protein, S cerevisiae; D000071190:Autophagy-Related Protein 8 Family; D000071183:Autophagy-Related Proteins; D008869:Microtubule-Associated Proteins; D010743:Phospholipids; D018160:Receptors, Cytoplasmic and Nuclear; D029701:Saccharomyces cerevisiae Proteins
keywords: autophagy; methylation; mitochondria; phospholipid; yeast