Mitochondrial Derived Compartments: Protecting Mitochondria From Nutrient Stress
Max-Hinderk Schuler1, Alyssa M. Litwiller1, Thomas Tedeschi1, Thane J. Campbell1, Janet M. Shaw1 and Adam L. Hughes1
1Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah USA
Mitochondria play a central role in cellular metabolism, and their functional decline is tied to a broad range of diseases. To maintain mitochondrial health in times of stress, cells utilize numerous quality control systems to protect mitochondria, including internal mitochondrial proteases, mitochondrial-derived vesicles, the ubiquitin-proteasome system, and mitophagy. Our lab recently discovered a new form of mitochondrial protein degradation, the mitochondrial-derived compartment (MDC) pathway, which selectively sorts and removes a subset of the mitochondrial proteome through formation of a novel, mitochondrial-associated membrane domain. However, the function of this pathway remains unclear. Here, we present new evidence suggesting that the MDC pathway is evolutionarily conserved from yeast to mammals and functions to protect mitochondria from excess nutrient stress. In support of this model, we show that MDC formation is triggered by elevated intracellular amino acids in both yeast and mammalian cells, whereas it is unresponsive to other common mitochondrial stressors, including ROS generators and membrane potential uncouplers. In response to elevated nutrients, MDCs selectively incorporate and remove inner membrane-embedded nutrient transporters of the SLC25A family, as well as outer membrane localized metabolite channels (mitochondrial porins), while leaving the remainder of the organelle intact. As the majority of mitochondrial metabolic reactions occur within the mitochondrial matrix, these nutrient transporters are responsible for nearly all metabolite exchange across mitochondrial membranes. Based on these results, we hypothesize that the MDC pathway removes nutrient transporters from mitochondria to limit or regulate metabolite flux across mitochondrial membranes in response to changes in cellular nutrient availability. Our current experiments are focused on testing this hypothesis, and identifying the machinery and metabolic signaling mechanisms that control selective sorting and removal of nutrient carriers from mitochondria via the MDC pathway.