Mitochondrial dynamics in health and disease
Our lab studies the basic mechanisms--including fusion-fission dynamics, degradation, and interactions with other organelles--that control mitochondrial function. We explore the role of mitochondrial dynamics in cellular physiology, development and human disease. In addition, we study other aspects of mitochondrial biology, including organellar quality control and biogenesis.
Introduction to mitochondriaMitochondria are organelles that act as the power generators of the eukaryotic cell, due to their efficient generation of ATP through oxidative phosphorylation (OXPHOS). In addition, mitochondria are the sites of the tricarboxylic acid (TCA) cycle, fatty acid oxidation, and numerous other metabolic pathways. However, mitochondria have functions far beyond energy metabolism—they play central roles in apoptosis, intracellular calcium handling, reactive oxygen species (ROS) generation and signaling, innate immunity, phospholipid synthesis, and iron-sulfur cluster biogenesis. Given these important functions, it is not surprising that dysfunction of mitochondria underlies many human diseases, particularly those of the nervous, cardiovascular, and muscular systems.
Unusual organellesMitochondria are thought to be descendants of an early procaryote that fused with an early eukaryote in an endosymbiotic event during evolution. Among organelles, mitochondria have several distinctive features. First, they are bounded by a double membrane. This membrane organization gives rise to several mitochondrial compartments or environments--the outer mitochondrial membrane, the intermembrane space, the inner mitochondrial membrane, and the matrix (the compartment encased by the inner membrane). In addition, the inner membrane is highly convoluted and folded, forming a membrane domain termed the cristae. Second, mitochondria contain their own genome, called mitochondrial DNA (mtDNA). The mtDNA is circular and encodes for 13 protein, 22 tRNAs, and 2 ribosomal RNAs. The latter two types of genes are used for the protein translation machinery of the mitochondria. All the protein-encoding mtDNA genes produce subunits of the OXPHOS machinery. Therefore, the OXPHOS machinery is unique in being composed of protein subunits encoded by both the nuclear and mitochondrial genomes. Although mitochondria have their own genome, it should be noted that the mitochondrial proteome, 1000-1500 proteins, is mostly encoded by the nucleus. Finally, mitochondria in humans are inherited maternally. As a consequence, mitochondrial diseases that are caused by mutations in mtDNA show a maternal pattern of inheritance, in contrast to mitochondrial disease caused by mutations in nuclear genes.
Mitochondria are highly dynamicOver a century ago, cell biologists discovered that mitochondria in cultured cells engage in fascinating behaviors. Cells have dozens or hundreds of mitochondria, and this population of organelles can be observed in live cells through the imaging of vital dyes that concentrate in mitochondria. Mitochondria were seen to collide into each other and fuse, sometimes forming interconnected networks; conversely, they were also seen to divide into separate organelles. Therefore, it appeared that mitochondria exist as a population of organelles that continually undergoes cycles of fusion and fission. The movement of mitochondria in the cytoplasm also suggested their transport along tracks. These tracks were later found to consist of various cytoskeletal filaments.
Mitochondrial dynamics refers to the dynamic nature of mitochondria and broadly encompasses the processes of fusion, fission, and transport. These processes impact virtually every function of mitochondria. Mitochondria are dynamic organelles that continually undergo fusion, fission, and trafficking. These fundamental cell biological processes control mitochondrial shape, number, size, distribution, and most importantly, physiology.