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
Affiliations
Jina Yun
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
Rajat Puri
Synaptic Functions Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States
Huan Yang
Department of Neurology, University of California, Los Angeles, Los Angeles, United States
Michael A Lizzio
Department of Neurology, University of California, Los Angeles, Los Angeles, United States
Chunlai Wu
Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, United States
Zu-Hang Sheng
Synaptic Functions Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States
Ming Guo
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
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.
