Mitochondria are essential energy-generating powerhouses and maintaining their function at optimal levels is critical for cell survival. Accumulation of dysfunctional mitochondria has been linked to many diseases including cancer, diabetes and neurodegenerative disorders such as Parkinson’s disease. Under normal circumstances our cells use a recycling pathway termed mitophagy to turnover such damaged mitochondria. However, we still do not fully understand how decisions are made by the cell to target functionally different pools of mitochondria.
As mitochondria are key for energy generation, they are critical under conditions of energy stress, which occurs under the pathological conditions mentioned above. Under such conditions it becomes important for the cell that only dysfunctional mitochondria undergo mitophagy whilst functional ones remain protected. How this happens within our cells is not clear but new work now sheds light on this process.
In a very productive three-way collaboration, Dundee’s Ganley Lab, with expertise in mitophagy, and the MacKintosh Lab, who work on the phosphoprotein-binding 14-3-3 proteins, teamed up with the Sakamoto Lab at the Novo Nordisk Foundation Center for Basic Metabolic Research (University of Copenhagen), who focus on AMP-activated protein kinase (AMPK), a master regulator of energy metabolism.
The work, spearheaded by former PhD student Marianna Longo and postdoctoral researcher Aniketh Bishnu, uncovered the mechanism behind this balance of mitophagy. They discovered that the protein kinase AMPK actively inhibits a mitophagy pathway that targets functioning mitochondria (the NIX pathway) by triggering a restraining 14-3-3 interaction with the mitophagy-initiating kinase ULK1. In contrast, they found that AMPK promotes a mitophagy pathway that targets damaged ones (the Parkin pathway) by bypassing ULK1 and directly phosphorylating and stimulating Parkin (a mitophagy regulator whose gene can be mutated in hereditary Parkinson’s). It is hoped that this work will help uncover cellular mechanisms that could be exploited therapeutically to help re-balance cellular mitochondrial pools that become misaligned in various disease states. The work, published in Molecular Cell can be read here.