Researchers from Osaka University identify a system known as the “GET pathway” as essential for efficient regulation of the numbers of energy-producing mitochondria
Osaka, Japan – A process known as “mitophagy” is responsible for the removal of mitochondria, the energy-producing parts of a cell. This occurs if they are defective, or to regulate their numbers. A protein anchored in the mitochondrial surface, called Atg32, promotes this process when it interacts with another protein, Atg11. Modification of Atg32 by “phosphorylation”—the attachment of a phosphate group—stabilizes the interaction between Atg32 and Atg11. The process by which this phosphorylation is regulated was unknown, but now a group from Osaka University has shown that a system known as the GET pathway is required for efficient mitophagy.
Mitophagy requires phosphorylation of Atg32 and a stable interaction between the Atg32 and Atg11 proteins. Mitophagy is suppressed by the action of a protein complex called the Ppg1–Far complex. This acts to reduce Atg32 phosphorylation and interaction with Atg11, and thus suppresses mitophagy.
Proteins located in membranes within the cell must be targeted to their appropriate destinations to maintain the functionality of the different cellular compartments. The GET pathway is responsible for inserting membrane proteins into the endoplasmic reticulum, which is a continuous and dynamic membrane system within the cell. When this pathway is disrupted, proteins can become predominantly inserted into the outer mitochondrial membrane instead.
The team first found that cells lacking the GET pathway showed reduced mitophagy. “This phenotype was rescued when cells lacked both the GET pathway and the Ppg1–Far complex,” explains first author Mashun Onishi, “indicating that the reduction in mitophagy that we observed is related to the activity of the Ppg1–Far complex.”
“We then went on to show that the GET pathway is responsible for tethering the Ppg1–Far complex at the endoplasmic reticulum membrane,” explains senior author Koji Okamoto, “preventing it from interacting with Atg32 to suppress mitophagy, thus allowing Atg32 activation and consequent interaction with Atg11.” In the absence of the GET pathway, however, the Ppg1–Far complex is instead targeted to the outer mitochondrial membrane, where it acts to suppress the process of mitophagy.
A protein called Msp1 acts to remove non-mitochondrial proteins from the mitochondrial membrane that have been located there. The team found that disruption of both GET and Msp1 resulted in more severe defects in mitophagy. This suggests that Msp1 might be responsible for removing incorrectly excessively localized Ppg1–Far from the mitochondria and thus maintaining the required levels of mitophagy.
Defects in the process of mitophagy can lead to cell death and have been implicated in aging and Alzheimer’s Disease. This work greatly increases our understanding of mitophagy and opens avenues for future research with a significant impact on human health.
The article, “The GET pathway serves to activate Atg32-mediated mitophagy by ER targeting of the Ppg1-Far complex”, was published in Life Science Alliance at DOI: https://www.life-science-alliance.org/content/6/4/e202201640
About Osaka University
Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan's most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.