Journal Article

Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy

Youle, Richard J, van der Bliek, Alexander M, Yamano, Koji, Fogel, Adam I, Wang, Chunxin

2014

Overview

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. Parkinson disease is a common degenerative brain disorder that causes tremors, muscle stiffening, and slowing down of movement. Scientists believe that these symptoms are caused by a progressive loss of brain cells called dopaminergic neurons, which help regulate movement. Most cases have no obvious genetic cause, but around 15% of people with the disease have a close relative who also has the disease, and mutations in the genes encoding two proteins—PINK1 and Parkin—have been identified as prime suspects in familial Parkinson disease. These proteins help to eliminate damaged mitochondria from cells. In addition to producing the energy that cells need to function, mitochondria also help to trigger cell death. Pesticides and other chemicals linked to non-familial cases of Parkinson disease also damage mitochondria. Taken together, this evidence suggests that the accumulation of damaged mitochondria may contribute to the excessive loss of dopaminergic neurons that is seen in both forms of the disease. Yamano et al. provide new details on the ways that autophagosomes—structures that help cells to recycle nutrients and remove debris—destroy mitochondria. Previous studies have shown that when a mitochondrion is damaged, PINK1 sends a signal to Parkin, which then helps to recruit the proteins that are needed to form an autophagosome around the damaged mitochondrion. However, the identity of the proteins that guide the formation of the autophagosome remained a mystery. Yamano et al. have now identified two of these proteins and helped to explain their specific roles in the assembly of autophagosomes. The two proteins, which are called TBC1D15 and TBC1D17, are both GAP proteins, which are well known for their role in deactivating enzymes called RAB GTPases. Yamano et al. show that TBC1D15 binds to the damaged mitochondrion and also to the autophagosome as it grows around the mitochondrion. TBC1D15 also inhibits the action of an enzyme called Rab7 to prevent excessive growth of the autophagosome. TBC1D17 has a similar role. The work of Yamano et al. indicates that Parkin activates Rab7, perhaps by placing chains of a protein called ubiquitin on mitochondria, which would mean that an unexpected new step in this pathway remains to be discovered. Understanding how Parkin activates Rab7 could help identify new targets for drugs that might treat Parkinson disease.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Apoptosis Regulatory Proteins / Autophagy / Autophagy-Related Protein 8 Family / Cell Biology / Cloning / Drp1 / Fis1 / GABARAP protein / Glycerol / GTPase-activating protein / GTPase-Activating Proteins - genetics / GTPase-Activating Proteins - metabolism / Guanosine triphosphatases / HCT116 Cells / HEK293 Cells / HeLa Cells / Humans / Lysosomes - metabolism / Lysosomes - pathology / Mammals / Membrane Proteins - genetics / Membrane Proteins - metabolism / Membranes / Microfilament Proteins - genetics / Microfilament Proteins - metabolism / Microscopy / Microtubule-Associated Proteins - genetics / Microtubule-Associated Proteins - metabolism / Microtubules - metabolism / Mitochondria / Mitochondria - enzymology / Mitochondria - pathology / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / Mitophagy / Morphogenesis / Morphology / Parkin / Parkin protein / Parkinson's disease / Protein Binding / Protein Multimerization / Proteins / PTEN-induced putative kinase / rab GTP-Binding Proteins - genetics / rab GTP-Binding Proteins - metabolism / rab7 / rab7 GTP-Binding Proteins / Signal Transduction / TBC1D15 / Time Factors / Transfection / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Ubiquitination / Yeast