Dissecting the Functional Interplay between Mitochondria and Lysosomes

Identification: Hughes, Casey


Description

 

Dissecting the Functional Interplay between Mitochondria and Lysosomes
 
Casey Hughes, Mi-Young Jeong, Dennis Winge, Adam Hughes
Department of Biochemistry, University of Utah

 
Mitochondria form functional and physical interactions with multiple cellular organelles, and disruption of these relationships leads to cellular toxicity and disease. One such well characterized inter-organelle connection exists between mitochondria and lysosomes. Lysosomes play vital roles in protein degradation, nutrient storage, and metabolic signaling, all of which require the lysosome to be acidified by the evolutionarily conserved Vacuolar-H+-ATPase. We and others have shown that disruption in V-ATPase function causes mitochondrial impairment, and that alterations in mitochondria-lysosome communication functions as a driver of aging and age-associated disorders such as Parkinson's Disease and Lysosomal Storage Disorders. Despite the longstanding connection between these organelles, we do not understand how lysosomes and mitochondrial are functionally linked, and why lysosome impairment leads to mitochondrial dysfunction. To address this question, we performed genetic screens in yeast to identify factors that uncouple the lysosome-mitochondrial relationship, and restore mitochondrial function in V-ATPase deficient cells. Through these screens, we found that genetic or pharmacologic enhancement of cellular iron uptake suppresses mitochondrial dysfunction in V-ATPase deficient cells.  These results strongly suggest that loss of lysosome function triggers mitochondrial impairment by disrupting cellular iron homeostasis. Consistent with this hypothesis, acute disruption of lysosomal function causes rapid iron starvation, inducing loss of iron-sulfur cluster containing respiratory chain complexes. We are now focused on understanding how alterations in lysosome function lead to iron disruption. One of the main functions of lysosomes is to sequester amino acids, and our current data suggests that compartmentation of cysteine by lysosomes is necessary to preserve cellular iron homeostasis and mitochondrial function. How accumulation of cytoplasmic cysteine in lysosome impaired cells disrupts iron utilization and mitochondrial function is currently unclear, and we are actively investigating this question. Overall, these results shed new light on the mitochondrial-lysosome relationship, and suggest that lysosomes sequester amino acids at least in part to preserve mitochondrial integrity.

 

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