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Mitochondrial Dynamics in Development and Disease

Research Summary

David Chan studies how the dynamic behaviors of mitochondria within a cell are controlled and how they affect cell and tissue physiology. These studies have implications for a broad range of human diseases, particularly neurological disorders.

Mitochondria are dynamic organelles that continually undergo fusion, fission, and trafficking (Figure 1 and Movie 1). These fundamental cell biological processes control mitochondrial shape, number, size, distribution, and physiology. We study the molecular basis for these dynamic properties and their impact on development and disease.

Molecular Mechanisms of Mitochondrial Dynamics
Mitochondrial fusion. Mitochondrial fusion is a membrane-remodeling process that coordinately merges the outer and inner membranes between two mitochondria. It requires three large GTPases: the mitofusins Mfn1 and Mfn2 and the dynamin-related protein OPA1 (Figure 2). Mitofusins are embedded in the mitochondrial outer membrane, whereas OPA1 is associated with the inner membrane. We have shown that mitofusins and OPA1 act at distinct steps during mitochondrial fusion: mitofusins are essential for outer membrane fusion, whereas OPA1 is required for inner membrane fusion. One of our main efforts is to understand the underlying mechanisms.

Mitochondrial fission. Mitochondrial fission requires the recruitment and assembly of the dynamin-related GTPase Drp1/Dnm1, which constricts the diameter of mitochondria (Figure 2). We are examining how Drp1/Dnm1 is recruited to the mitochondrial surface via a number of mitochondrial transmembrane receptors. The resolution of this issue is important, because mitochondrial fission is essential for several cellular functions, including apoptosis, programmed necrosis, mitochondrial distribution, and mitochondrial degradation by autophagy. Our long-term goals are to understand the atomic structure of the fission complexes, to determine how they are activated for fission, and to identify currently unknown members of the mammalian fission machinery.

Movie 1: Mitochondrial dynamics in a mouse fibroblast. This movie shows a portion of a mouse embryonic fibroblast in which the mitochondria are labeled with mitochondrially targeted yellow fluorescent protein. The mitochondria have diverse morphologies and travel along their long axes. Two pairs of mitochondria come together end-to-end and fuse, followed by a fission event.

Adapted from Chen, H., Detmer, S.A., Ewald, A.J., Griffin, E.E., Fraser, S.E., and Chan, D.C. 2003. Journal of Cell Biology 160:189–200.

Cellular Functions of Mitochondrial Dynamics
At the cellular level, a major issue is why cells maintain their mitochondria in a dynamic state. One clearly established reason is that a dynamic equilibrium between fusion and fission regulates the morphology of mitochondria. Cells do not, however, require high levels of fusion and fission to maintain tubular mitochondria, suggesting that there are additional reasons why mitochondria are such dynamic organelles.

We found that fusion is an important quality control mechanism for mitochondria. Fusion-deficient cells have greatly diminished respiratory capacity and reduced cell growth. In addition, the mitochondrial population shows heterogeneous properties, including wide variations in membrane potential. On the basis of these observations, we propose that mitochondria do not function well as autonomous organelles and that the dynamic property of mitochondria is inherently important for organelle integrity. In normal cells, high rates of fusion and fission enable mitochondria to cooperate with each other through continual exchange of contents. Individual mitochondria can stochastically lose essential components, but such defects are short-lived because mitochondrial fusion will restore the missing components from neighboring mitochondria. In cells lacking mitochondrial fusion, such restoration of activity cannot occur, and defective mitochondria accumulate. We recently discovered that, in the absence of fusion, a large population of mitochondria lack mitochondrial DNA (mtDNA) nucleoids. Therefore, mitochondrial fusion is essential to provide defective mitochondria a pathway to recover mtDNA. This defect explains the respiratory and membrane potential aberrations found in fusion-deficient cells.

Although the machineries mediating mitochondrial fusion and fission are being elucidated, little is known about how mitochondrial dynamics is regulated. An understanding of this regulation is important, given the dramatic changes in mitochondrial dynamics that occur with cellular stress, activity, and apoptosis. We are using biochemical and genetic approaches to identify cellular processes that regulate the activity of the mitochondrial fusion and fission complexes.

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 genesMfn2 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 found that mice with mutations in mitochondrial dynamics genes have a variety of neuromuscular defects. For example, animals lacking Mfn2 have severe degeneration of Purkinje neurons in the cerebellum (Figure 3) and dopaminergic neurons of the substantia nigra (the region of the brain affected in Parkinson’s disease). We traced these defects to mitochondrial fragmentation, respiratory dysfunction, and impaired mitochondrial transport within the neuronal processes. We also found that the mitofusins are essential for maintenance of skeletal muscle. With these animal models, and the cellular systems derived from them, we can now further dissect the mechanistic link between mitochondrial dynamics and neuromuscular disease.

Natural History of mtDNA Mutations and Aging
Although the mitochondrial genome is small, 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, older individuals have clonal mtDNA deletions and respiratory loss in individual substantia nigra neurons, a finding that has implications for Parkinson's disease.

We 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.

This work is supported in part by grants from the National Institutes of Health.

As of December 19, 2012

Scientist Profile

California Institute of Technology
Biochemistry, Cell Biology