Phospholipid methylation controls Atg32-mediated mitophagy and Atg8 recycling

Kaori Sakakibara, Akinori Eiyama, Sho W. Suzuki, Machiko Sakoh-Nakatogawa, Nobuaki Okumura, Motohiro Tani, Ayako Hashimoto, Sachiyo Nagumo, Noriko Kondo-Okamoto, Chika Kondo-Kakuta, Eri Asai, Hiromi Kirisako, Hitoshi Nakatogawa, Osamu Kuge, Toshifumi Takao, Yoshinori Ohsumi, Koji Okamoto

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2703-2719
Number of pages17
JournalEMBO Journal
Volume34
Issue number21
DOIs
Publication statusPublished - Nov 3 2015

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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