The Role of Mitochondrial Dynamics in Human Disease
Human genetic studies indicate that neurons are particularly sensitive to defects in mitochondrial dynamics. Mutations in the mitochondrial fusion genes Mfn2 and OPA1 cause the neurodegenerative diseases Charcot-Marie-Tooth type 2A and dominant optic atrophy. In addition, several major neurodegenerative diseases—including Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease—are associated with defects in mitochondrial dynamics. One of our major goals, therefore, is to identify the cellular mechanisms leading to neurodegeneration when mitochondrial fusion is perturbed.
We have found that mice with mutations in mitochondrial dynamics genes have a variety of neuromuscular defects. For example, animals lacking Mfn2have severe degeneration of Purkinje neurons in the cerebellum and dopaminergic neurons of the substantia nigra (the region of the brain affected in Parkinson’s disease). We have traced these defects to mitochondrial fragmentation, respiratory dysfunction, and impaired mitochondrial transport within the neuronal processes. We have also found that the mitofusins are essential for proper maintenance of skeletal muscle and the male germline. With these animal models, and the cellular systems derived from them, we can now further dissect the mechanistic link between mitochondrial dynamics, normal physiology and neuromuscular disease.
The Natural History of mtDNA Mutations and Aging
Although the mitochondrial genome is tiny at only 16.5 kilobases, a remarkable number of human disorders are related to mutations in mtDNA. For example, most mitochondrial encephalomyopathies are caused by mutations in mtDNA. A characteristic feature of these diseases is their progressive nature. This age-related progression has been attributed to the stochastic nature of mtDNA inheritance during cell division. As the load of mutant mtDNA increases, the bioenergetic threshold of specific cells is breached, and cellular dysfunction ensues.
Accumulation of mutations in mtDNA may also be involved in aging. Many studies have documented a progressive age-related decline in respiratory function in muscle and brain. For example, aged individuals have clonal mtDNA deletions and respiratory loss in individual substantia nigra neurons, a finding that has implications for Parkinson's disease.
We have found that mitochondrial fusion is required for the ability of mammalian cells to tolerate high loads of mtDNA mutations. Mitochondrial fusion promotes content mixing between mitochondria and enables complementation of mtDNA mutations. Therefore, mitochondrial dynamics may be a protective factor in disorders associated with mtDNA mutations.