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PMID: 24569479 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Video-Audio Media

Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy.

eLife ·Vol. 3 ·2014-02-25 ·Pages e01612

Yamano K, Fogel AI, Wang C, van der Bliek AM, Youle RJ

Abstract

Damaged mitochondria can be selectively eliminated by mitophagy. Although two gene products mutated in Parkinson's disease, PINK1, and Parkin have been found to play a central role in triggering mitophagy in mammals, how the pre-autophagosomal isolation membrane selectively and accurately engulfs damaged mitochondria remains unclear. In this study, we demonstrate that TBC1D15, a mitochondrial Rab GTPase-activating protein (Rab-GAP), governs autophagosome biogenesis and morphology downstream of Parkin activation. To constrain autophagosome morphogenesis to that of the cargo, TBC1D15 inhibits Rab7 activity and associates with both the mitochondria through binding Fis1 and the isolation membrane through the interactions with LC3/GABARAP family members. Another TBC family member TBC1D17, also participates in mitophagy and forms homodimers and heterodimers with TBC1D15. These results demonstrate that TBC1D15 and TBC1D17 mediate proper autophagic encapsulation of mitochondria by regulating Rab7 activity at the interface between mitochondria and isolation membranes. DOI: http://dx.doi.org/10.7554/eLife.01612.001.

Keywords
Drp1 Fis1 Parkin TBC1D15 autophagy rab7
MeSH Terms
Adaptor Proteins, Signal Transducing/genetics,metabolism Apoptosis Regulatory Proteins Autophagy Autophagy-Related Protein 8 Family GTPase-Activating Proteins/genetics,metabolism HCT116 Cells HEK293 Cells HeLa Cells Humans Lysosomes/metabolism,pathology Membrane Proteins/genetics,metabolism Microfilament Proteins/genetics,metabolism Microtubule-Associated Proteins/genetics,metabolism Microtubules/metabolism Mitochondria/enzymology,pathology Mitochondrial Proteins/genetics,metabolism Mitophagy Protein Binding Protein Multimerization Signal Transduction Time Factors Transfection Ubiquitin-Protein Ligases/genetics,metabolism Ubiquitination rab GTP-Binding Proteins/genetics,metabolism rab7 GTP-Binding Proteins
Chemicals
Adaptor Proteins, Signal Transducing Apoptosis Regulatory Proteins Autophagy-Related Protein 8 Family FIS1 protein, human GABARAP protein, human GABARAPL2 protein, human GTPase-Activating Proteins MAP1LC3A protein, human Membrane Proteins Microfilament Proteins Microtubule-Associated Proteins Mitochondrial Proteins TBC1D15 protein, human TBC1D17 protein, human rab7 GTP-Binding Proteins rab7 GTP-binding proteins, human Ubiquitin-Protein Ligases parkin protein rab GTP-Binding Proteins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Yamano Koji
Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.
Fogel Adam I
Wang Chunxin
van der Bliek Alexander M
Youle Richard J
Conflict of Interest

RJY: Reviewing editor, eLife. The other authors declare that no competing interests exist.

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Article Info
Journal
eLife
Abbr.
Elife
ISSN
2050-084X
DOI
10.7554/eLife.01612
Published
2014-02-25
Epub
2014-00-25
Pages
e01612
Language
English
Region
England
NLM ID
101579614
PMCID
PMC3930140
Subset
IM
Grants
NIGMS NIH HHS · GM051866 · United States
External Links
PubMed source DOI: 10.7554/eLife.01612 PMC Full Text View journal details
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