Dynamic Internal Spatial Organization of Mitochondria

Project Summary Mitochondria are double membrane-bound organelles that perform many crucial cellular functions, including nucleotide and amino acid metabolism, cellular Ca2+ homeostasis, and their most well-known function, generation of cellular energy via oxidative phosphorylation. To perform these diverse functions, the mitochondrial interior is elaborately physically organized. Mitochondria are also distributed throughout cells as part of a dynamic, semi-continuous network that divides and fuses in part to distribute the mitochondrial genome. Correct mitochondrial organization and distribution are critical for cellular function, and defects in processes that maintain mitochondrial architecture can result in a large number of diseases, including neurodegeneration and diabetes. Despite the complicated nature of mitochondrial structure, we have a minimal mechanistic understanding of how cellular metabolic needs are communicated to the interior of the organelle and how mitochondrial organization is dynamically modulated to meet this demand. In the next project period, our goal is to address this deficit by studying three distinct aspects of mitochondrial communication and internal remodeling. We will examine how mitochondrial structure is coordinated across the two mitochondrial membranes during mitochondrial fission (Direction 1), how mitochondria internal organization is remodeled to support local subcellular metabolic demand (Direction 2), and how the interior of the organelle can sense and respond to acute localized stress and communicate this dysfunction to external quality control machinery (Direction 3). This work will lead to insight into the spatial organization and form-function relationship of mitochondria and give us molecular understanding of the disorganization and dysfunction of mitochondrial membranes that frequently occurs in human disease.