Regulation of mitochondrial morphology and functional versatility

PROJECT SUMMARY Eukaryotic cells sequester critical biochemical reactions into discrete membranous compartments, whereby membrane dynamics driven by protein catalysts facilitate differentiation, communication, and spatial organization of intracellular compartments. Within a cell, mitochondria are mainly organized into highly interconnected networks, whose diverse functions are dependent on their complex structure and organization. In humans, OPA1 and MICOS are essential biomolecular machines that control not only the morphology of the mitochondrial reticulum, but also the efficiency of many key mitochondrial processes, including oxidative phosphorylation, metabolism, apoptosis, and mtDNA maintenance. The GTPase OPA1 is crucial for mitochondrial IM fusion and regulating cristae dynamics, whereas the multi-component MICOS complex plays a dual role by shaping IM cristae junctions and forming contact sites with the outer membrane. Characterizing how mitochondrial dynamics are realized and regulated will be essential to deciphering the link between mitochondrial morphology and function. Moreover, molecular abnormalities in mitochondrial dynamics result in aberrant mitochondrial structure, impaired bioenergetics, severely reduced respiratory capacity, mtDNA instability, increased sensitivity to apoptosis, and development of a wide variety of disease conditions, including neurodegenerative disorders, diverse cancers, obesity, and cardiovascular diseases. Yet, the molecular mechanisms that alter mitochondrial morphology and function remain incompletely understood. Here, using a combination of cellular and structural analyses, we aim to develop a molecular understanding of mitochondrial dynamics that govern key physiological processes in cells. We propose to determine the molecular mechanism of mitochondrial morphogenesis by exploring the assembly mechanism of OPA1 and its interactions with the mitochondrial lipid cardiolipin (Aim 1). We further propose to characterize the molecular details of multi-component MICOS complex and protein dynamics that facilitate cristae formation and maintain the characteristic architecture of mitochondria (Aim 2). Structural and functional studies of mitochondrial protein machines will provide a platform to identify the basis of pathologies linked to human disease and age-related illness. Understanding the precise molecular mechanisms of mitochondrial dynamics will increase the probability of success in developing new therapeutic interventions.