CELLULAR FUNCTIONS OF MITOCHONDRIAL DYNAMICS
The dynamic properties of mitochondria control almost every aspect of their function. Exchange of membranes and contents is critical for maintaining a healthy population of mitochondria.
Eukaryotic cells, such as hepatocytes, can have hundreds of mitochondria. However, each mitochondrion is not an isolated, autonomous organelle. Mitochondria within the population are dynamic and continually fuse and divide, leading to exchange of membranes and internal contents. Why do cells expend energy to maintain their mitochondria in such a dynamic state? One clearly established reason is that the equilibrium between fusion and fission rates regulates mitochondrial morphology, which typically manifests as a mixture of tubules and spheres. Cells with unopposed fusion have overly long and interconnected mitochondrial tubules; conversely, cells with unopposed fission have fragmented mitochondria. Such changes in morphology can indeed affect mitochondrial function, but dynamics also regulates mitochondrial physiology through mechanisms besides morphology.
We have found that it is the balance between fusion and fission, rather than their absolute rates, that is important for mitochondrial physiology. Defects in mitochondrial physiology arise when these rates are unbalanced. Fusion-deficient cells have greatly diminished respiratory capacity and reduced cell growth. In addition, the mitochondrial population becomes heterogeneous, with individual organelles showing wide variations in membrane potential, mitochondrial DNA content and protein constituents. Based on these observations, it is clear that mitochondria do not function well as autonomous organelles and that the dynamic properties of mitochondria are inherently important for organellar integrity. In normal cells, high rates of fusion and fission enable mitochondria to cooperate with each other through continual exchange of contents. When mitochondrial fusion-fission dynamics is robust, fluctuations in features are short-lived, because mitochondrial fusion will result in mixing and normalization of components. In cells lacking mitochondrial fusion, such restoration of components cannot occur, and defective mitochondria accumulate. We discovered that, in the absence of fusion, many mitochondria lack mitochondrial DNA (mtDNA) nucleoids. This defect explains the respiratory chain and membrane potential aberrations found in fusion-deficient cells.
Although the machineries mediating mitochondrial fusion and fission have been identified, much more needs to be understood about how mitochondrial dynamics is regulated. Dramatic changes in mitochondrial dynamics occur with cellular stress, activity, apoptosis, and disease. We are using biochemical and genetic approaches to identify cellular processes that regulate the activity of the mitochondrial fusion and fission complexes. We are also studying how these activities are coordinated with other cellular events, including stress signaling, mitophagy, and reorganization of the cytoskeleton.
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