Maintaining mitochondrial homeostasis during stress

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Mitochondria are essential organelles that provide cells with energy and numerous metabolites such as lipids, amino acids, iron-sulfur clusters, and heme. These organelles are semi-autonomous; they contain a genome but most of their proteome is encoded by the nucleus. Therefore, one of the most fundamental processes in maintaining mitochondrial functions is the import of proteins into the organelle. Protein import into the mitochondria is a complexed process, which can be challenged by cellular and environmental changes. Indeed, disturbances in mitochondrial protein import are common under physiological conditions such as oxidative stress, increased demand for energy, and aging. Although the mechanism governing protein import into mitochondria is well understood, little is known regarding how defects in this process are sensed and repaired by the cell. My long-term goal is to reveal how impaired mitochondrial protein import is repaired in budding yeast, both at the cellular and molecular levels. My previous studies showed that when protein import slows down, mitochondrial proteins accumulate in the import channels and clog the mitochondrial import machinery. I found that cells have evolved to cope with this stress by activating a transcriptional response - the mitochondrial compromised protein import response (mitoCPR). MitoCPR facilitates eviction of stalled proteins from the mitochondrial surface, and therefore restores mitochondrial functions during import stress. Many open questions remain regarding the roles and mechanisms of mitoCPR during import stress. Using a combination of biochemistry, genetics, and cell biology in yeast cells, my short-term research program will focus on two aims: 1. To elucidate the mitoCPR mechanisms of mitochondrial protein quality control; 2. To identify novel cellular pathways and factors that prevent mitochondrial damage during stress. In summary, my research program will advance our understanding of how proper mitochondrial functions are maintained, by revealing the mechanisms which control mitochondrial health. The essentiality of mitochondria in many metabolically active tissues and physiological processes is conserved across eukaryotes. Therefore, I envision a broad impact of this research on numerous scientific fields such as developmental biology, cell biology, and metabolism.