FKBP8 LIRL-dependent mitochondrial fragmentation facilitates mitophagy under stress conditions.
FKBP8
OPA1
mitochondria fission
mitophagy
stress
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
11
07
2019
revised:
02
12
2019
accepted:
15
12
2019
pubmed:
8
1
2020
medline:
30
9
2020
entrez:
8
1
2020
Statut:
ppublish
Résumé
Mitochondrial quality control maintains mitochondrial function by regulating mitochondrial dynamics and mitophagy. Despite the identification of mitochondrial quality control factors, little is known about the crucial regulators coordinating both mitochondrial fission and mitophagy. Through a cell-based functional screening assay, FK506 binding protein 8 (FKBP8) was identified to target microtubule-associated protein 1 light chain 3 (LC3) to the mitochondria and to change mitochondrial morphology. Microscopy analysis revealed that the formation of tubular and enlarged mitochondria was observed in FKBP8 knockdown HeLa cells and the cortex of Fkbp8 heterozygote-knockout mouse embryos. Under iron depletion-induced stress, FKBP8 was recruited to the site of mitochondrial division through budding and colocalized with LC3. FKBP8 was also found to be required for mitochondrial fragmentation and mitophagy under hypoxic stress. Conversely, FKBP8 overexpression induced mitochondrial fragmentation in HeLa cells, human fibroblasts and mouse embryo fibroblasts (MEFs), and this fragmentation occurred in Drp1 knockout MEF cells, FIP200 knockout HeLa cells and BNIP3/NIX double knockout HeLa cells, but not in Opa1 knockout MEFs. Interestingly, we found an LIR motif-like sequence (LIRL), as well as an LIR motif, at the N-terminus of FKBP8 and LIRL was essential for both inducing mitochondrial fragmentation and binding of FKBP8 to OPA1. Together, we suggest that FKBP8 plays an essential role in mitochondrial fragmentation through LIRL during mitophagy and this activity of FKBP8 together with LIR is required for mitophagy under stress conditions.
Identifiants
pubmed: 31908024
doi: 10.1096/fj.201901735R
doi:
Substances chimiques
FKBP8 protein, human
0
Fkbp8 protein, mouse
0
MAP1LC3A protein, human
0
Map1lc3b protein, mouse
0
Microtubule-Associated Proteins
0
Tacrolimus Binding Proteins
EC 5.2.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2944-2957Informations de copyright
© 2019 Federation of American Societies for Experimental Biology.
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