Regulation and physiologic functions of GTPases in mitochondrial fusion and fission in mammals.

SIGNIFICANCE: Mitochondria are double membrane-bound organelles with tubular network structures that are essential for oxidative ATP production and play pivotal roles in regulating calcium homeostasis and apoptosis. Furthermore, mitochondria produce large amounts of reactive oxygen species that are fatal to cellular functions through uncoupled respiration. These organelles dynamically change their morphology by frequent fusion and fission, and three types of high molecular weight GTPase proteins have been identified as core components of the fusion and fission machineries. RECENT ADVANCES: Here, we review recent advances in the study of mitochondrial fission and fusion GTPases and their physiologic roles in mammalian cells. The regulation of mitochondrial dynamics coupled with a quality control system is essential for cellular homeostasis, development, and tissue differentiation. Defects of these mechanisms cause various disorders, including neurodegenerative diseases, such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. CRITICAL ISSUES: Although a significant amount of relevant data has accumulated on the regulation of mammalian mitochondrial fusion and fission, mechanistic molecular details and cellular functions still remain insufficiently defined. FUTURE DIRECTIONS: Elucidating the physiologic roles of mitochondrial fusion and fission in highly differentiated cells using tissue-specific knockout mice remains a challenge for the future.