Defining intracellular mitochondrial heterogeneity establishment and maintenance

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Project Summary Mitochondria are the subcellular compartment responsible for a majority of cellular metabolic events including oxidative phosphorylation, heme biosynthesis, and other metabolic fluxes. Given the common depictions of mitochondrial physiology, it is striking that two recent studies have discovered subsets of mitochondria that are specialized in their functions and composition (2,10). In accordance with these findings, we posit the innovative hypothesis that intracellular mitochondrial heterogeneity exists in cells and is maintained through intracellular organelle-communication. In this proposal, we will define intracellular mitochondrial heterogeneity and discover the characteristics of specialized mitochondria. Using independent techniques: 1) CRISPR-mediated endo- tagging of select mitochondrial protein; 2) Proximity labeling and affinity purification of mitochondria, isolated mitochondrial populations will undergo comparative proteomics and metabolomics with Steven Gygi (see attached letter). A potential mechanism to establish mitochondrial heterogeneity in cells is to have distinct modes of intracellular communication. In this context, we propose that organelle proximity (ER, Golgi, peroxisome, lysosome, endosome, and lipid droplets) is necessary for the establishment and maintenance of specialized mitochondria by changing their individual proteomes and thus, mitochondrial function and metabolism. Additionally, we aim to uncover the roles for intracellular mitochondrial heterogeneity in cellular homeostasis. Overall, the insights gained from the proposed experiments will provide an innovative and exciting perspective on mitochondrial biology and homeostasis.