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

Jina Yun; Rajat Puri; Huan Yang; Michael A Lizzio; Chunlai Wu; Zu-Hang Sheng; Ming Guo

doi:10.7554/eLife.01958

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

Elife. 2014 Jun 4:3:e01958. doi: 10.7554/eLife.01958.

Authors

Jina Yun¹, Rajat Puri², Huan Yang³, Michael A Lizzio³, Chunlai Wu⁴, Zu-Hang Sheng², Ming Guo⁵

Affiliations

¹ Department of Neurology, University of California, Los Angeles, Los Angeles, United States Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States.
² Synaptic Functions Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.
³ Department of Neurology, University of California, Los Angeles, Los Angeles, United States.
⁴ Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, United States.
⁵ Department of Neurology, University of California, Los Angeles, Los Angeles, United States Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States Brain Research Institute, The David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States mingfly@ucla.edu.

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.DOI: http://dx.doi.org/10.7554/eLife.01958.001.

Keywords: MUL1; PINK1; Parkinson's disease; mitochondria; parkin; ubiquitin ligase.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Genetically Modified
Cerebral Cortex / enzymology
Drosophila Proteins / genetics
Drosophila Proteins / metabolism*
Drosophila melanogaster / enzymology*
Drosophila melanogaster / genetics
Genotype
HeLa Cells
Humans
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mitochondria / enzymology*
Mitochondria / pathology
Mitophagy*
Mutation
Neurons / enzymology
Phenotype
Protein Binding
Protein Kinases / genetics
Protein Kinases / metabolism
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
RNA Interference
Signal Transduction*
Time Factors
Transfection
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination

Substances

Drosophila Proteins
Marf protein, Drosophila
Membrane Proteins
MUL1 protein, human
Ubiquitin-Protein Ligases
mitochondrial ubiquitin ligase 1, Drosophila
parkin protein
Protein Kinases
PINK1 protein, Drosophila
PTEN-induced putative kinase
Protein Serine-Threonine Kinases
park protein, Drosophila

Abstract

Publication types

MeSH terms

Substances

Grants and funding