Selective escape of proteins from the mitochondria during mitophagy.
Mitophagy refers to the degradation of mitochondria by the autophagy system that is regulated by Parkin and PINK1, mutations in the genes for which have been linked to Parkinson's disease. Here we show that certain mitochondrial outer membrane proteins, including FKBP38 and Bcl-2, translocate from the mitochondria to the endoplasmic reticulum (ER) during mitophagy, thereby escaping degradation by autophagosomes. This translocation depends on the ubiquitylation activity of Parkin and on microtubule polymerization. Photoconversion analysis confirmed that FKBP38 detected at the ER during mitophagy indeed represents preexisting protein transported from the mitochondria. The escape of FKBP38 and Bcl-2 from the mitochondria is determined by the number of basic amino acids in their COOH-terminal signal sequences. Furthermore, the translocation of FKBP38 is essential for the suppression of apoptosis during mitophagy. Our results thus show that not all mitochondrial proteins are degraded during mitophagy, with some proteins being evacuated to the ER to prevent unwanted apoptosis.
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
Shotaro
S
Saita
Michiko
M
Shirane
Keiichi I
KI
Nakayama
D000595:Amino Acid Sequence; D000818:Animals; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000166:cytology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism*; D063306:Mitophagy / Q000187:drug effects; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C119437:Fkbp8 protein, mouse; D024101:Mitochondrial Proteins; D050505:Mutant Proteins; D051020:bcl-X Protein; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex; D022021:Tacrolimus Binding Proteins