Research Projects

Skeletal muscles exhibit remarkable diversity in their metabolic and contractile properties, requiring precise coordination between organelle organization and muscle fiber-type specification. The endoplasmic reticulum (ER) and mitochondria communicate through specialized contact sites (MERCs) crucial for calcium homeostasis and energy metabolism. However, how these organelle interactions influence muscle fiber-type determination and maintenance remains poorly understood. Our previous work identified that the transcription factor Spalt major (Salm) regulates both fiber-type identity and mitochondrial organization in muscles, and we discovered that the mitochondrial fusion factor Opa1 controls MERC architecture in both fly and mammalian muscles, demonstrating evolutionary conservation of these regulatory mechanisms. Our proposal will investigate the molecular mechanisms governing mitochondrial organization and communication with ER in muscle health and disease, through six interconnected objectives: (1.1) Determine how salm regulates ER biogenesis and organization during muscle-type specification, (1.2) Test whether ER distribution dictates mitochondrial amount, size, and position in muscle types, and (1.3) Identify factors regulating mitochondrial biogenesis in oxidative versus glycolytic muscles. (2.1) Determine how MERC enhancement influences mitochondrial structure and function (2.2) Evaluate how enhanced MERC abundance influences muscle structure and function during aging, and (2.3) Determine how Type 2 diabetes affects mitochondrial dynamics and MERC organization in muscles. Using Drosophila genetics, combined with high-resolution microscopy, live imaging, and proteomic approaches, we will investigate the temporal sequence of mitochondrial and ER remodeling during muscle-type specification and examine how manipulating MERC abundance affects muscle function in aging and metabolic disease. Additionally, our research will provide fundamental insights into how organelle communication influences muscle type specification and maintenance. By elucidating the molecular mechanisms governing ER-mitochondria organization across muscle types and during aging, our findings will establish the foundation for therapeutic strategies targeting organelle interactions to combat age-related muscle decline and metabolic disorders. The technical and genetic tools developed through this study will benefit the broader cell biology community investigating organelle dynamics in development and disease. Furthermore, our research explores how communication between cellular compartments (mitochondria and ER) influences muscle function and health. Understanding how these interactions are established and maintained will help develop new treatments for age-related muscle weakness and metabolic diseases like diabetes, potentially improving the quality of life for millions of affected individuals.