Autophagy-mediated turnover of dynamin-related protein 1

Drp1 is the primary protein responsible for mitochondrial fission. Perturbations of mitochondrial morphology and increased fission are seen in neurodegeneration. While Drp1 degradation induced by Parkin overexpression can be prevented by proteasome inhibition, there are numerous links between protea...

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Bibliographic Details
Published in:BMC neuroscience 2013-08, Vol.14 (1), p.86-86, Article 86
Main Authors: Purnell, Phillip R, Fox, Howard S
Format: Article
Language:English
Subjects:
Analysis
Animals
Autophagy
Autophagy (Cytology)
Autophagy - drug effects
Autophagy - genetics
Autophagy - physiology
Autophagy-Related Protein 7
Cells, Cultured
Cellular proteins
Corpus Striatum - cytology
Dynamins
Embryo, Mammalian
Enzyme Inhibitors - pharmacology
Experiments
Gene Expression Regulation - drug effects
Gene Expression Regulation - genetics
Gene Expression Regulation - physiology
Green Fluorescent Proteins - genetics
Green Fluorescent Proteins - metabolism
GTP Phosphohydrolases - genetics
GTP Phosphohydrolases - metabolism
Humans
Microtubule-Associated Proteins - genetics
Microtubule-Associated Proteins - metabolism
Mitochondria
Mitochondria - drug effects
Mitochondria - metabolism
Mitochondrial Proteins - genetics
Mitochondrial Proteins - metabolism
Mutation
Neurodegeneration
Neurons
Neurons - drug effects
Neurons - metabolism
Oxazines - pharmacology
Physiological aspects
Proteins
Rats
RNA, Small Interfering - metabolism
Time Factors
Transfection
Ubiquitin-Activating Enzymes - genetics
Ubiquitin-Activating Enzymes - metabolism
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Summary:Drp1 is the primary protein responsible for mitochondrial fission. Perturbations of mitochondrial morphology and increased fission are seen in neurodegeneration. While Drp1 degradation induced by Parkin overexpression can be prevented by proteasome inhibition, there are numerous links between proteasomal and autophagic processes in mitochondrial protein degradation. Here we investigated the role of autophagy in Drp1 regulation. We demonstrate that autophagy plays a major role in the control of Drp1 levels. In HEK-293T cells, inhibitors of autophagy increase total Drp1 and levels of Drp1 in the mitochondrial cellular fraction. Similarly by silencing ATG7, which is required for initiation of autophagy, there is an increased level of Drp1. Because of the role of increased Drp1 in neurodegeneration, we then examined the ability to modulate Drp1 levels in neurons by inducing autophagy. We are able to decrease Drp1 levels in a time- and dose-dependent manner with the potent neuronal autophagy inducer 10-NCP, as well as structurally related compounds. Further, 10-NCP was able increase average mitochondrial size and length verifying a functional result of Drp1 depletion in these neurons. These pharmacological and genetic approaches indicate that autophagy targets Drp1 for lysosomal degradation. Additionally these data suggest a mechanism, through Drp1 downregulation, which may partly explain the ability of autophagy to have a neuroprotective effect.
ISSN:1471-2202
1471-2202
DOI:10.1186/1471-2202-14-86