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MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin

Yun, Jina, Puri, Rajat, Yang, Huan, Lizzio, Michael A, Wu, Chunlai, Sheng, Zu-Hang, Guo, Ming·2014·eLife
DOI 10.7554/elife.01958PMC PMC4044952
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Abstract

Parkinson's disease (PD) genes PINK1 and parkin act in a common pathway that regulates mitochondrial integrity and quality. Identifying new suppressors of the pathway is important for finding new therapeutic strategies. In this study, we show that MUL1 suppresses PINK1 or parkin mutant phenotypes in Drosophila. The suppression is achieved through the ubiquitin-dependent degradation of Mitofusin, which itself causes PINK1/parkin mutant-like toxicity when overexpressed. We further show that removing MUL1 in PINK1 or parkin loss-of-function mutant aggravates phenotypes caused by loss of either gene alone, leading to lethality in flies and degeneration in mouse cortical neurons. Together, these observations show that MUL1 acts in parallel to the PINK1/parkin pathway on a shared target mitofusin to maintain mitochondrial integrity. The MUL1 pathway compensates for loss of PINK1/parkin in both Drosophila and mammals and is a promising therapeutic target for PD.

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Metadata

Authors
Yun, J., Puri, R., Yang, H., Lizzio, M. A., Wu, C., Sheng, Z.-H., & Guo, M.
Affiliations
  • Department of Neurology, University of California, Los Angeles, Los Angeles, United States
  • Synaptic Functions Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States
  • Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, United States
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2014-06-04
Volume
3
ISSN
2050-084X
DOI
10.7554/elife.01958
PMC
PMC4044952
Cited by
303
References
17
Language
en
Licence
Funders
  • McKnight Endowment Fund for Neuroscience
  • National Institutes of Health (R01, K02, P01)
  • Ellison Medical Foundation (Senior Scholar Award)
  • Esther A. and Joseph Klingenstein Fund (Klingenstein-Simons Fellowship Award in Neurosciences)
  • The American Parkinson Disease Association
  • Glenn Family Foundation
  • National Institute of Neurological Disorders and Stroke (Intramural research program)
  • The Chinese Scholarship Council Fellowship
  • NIH-DBT Khorana Nirenberg Scholarship
  • UCLA Dissertation Fellowship

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