Cellular Functions of Mitochondrial Dynamics

Eukaryotic cells, such as hepatocytes, can contain hundreds of mitochondria. Yet these organelles do not function as isolated, autonomous units. Instead, they exist as a highly dynamic population that continually undergoes fusion and fission, exchanging membranes and internal contents. Why do cells invest energy in maintaining this dynamism? One well-established reason is that the balance between fusion and fission shapes mitochondrial morphology, producing the characteristic mixture of tubules and spheres seen in most cells. When fusion predominates, mitochondria become excessively elongated and interconnected; when fission is unopposed, they fragment into small units. Morphology can influence function, but mitochondrial dynamics also regulates physiology through additional mechanisms.

Our work has shown that it is the balance between fusion and fission—not their absolute rates—that is essential for mitochondrial health. When this balance is disrupted, mitochondrial physiology breaks down. Fusion-deficient cells exhibit severely reduced respiratory capacity and diminished growth, and their mitochondrial populations become heterogeneous, with large cell-to-cell and organelle-to-organelle variations in membrane potential, mitochondrial DNA (mtDNA) content, and protein composition. These findings support the view that mitochondria do not operate effectively as independent organelles: their dynamic behavior is crucial for maintaining integrity. In normal cells, frequent fusion and fission allow mitochondria to share and equilibrate components, buffering against stochastic fluctuations in mtDNA, proteins, or metabolites. Without continuous content exchange, these fluctuations cannot be corrected, causing defective mitochondria to accumulate. Indeed, we have found that many mitochondria in fusion-deficient cells lose their mtDNA nucleoids, explaining their impaired respiratory chain function and altered membrane potential.

Although the core fusion and fission machineries have been identified, much remains to be learned about how mitochondrial dynamics is regulated. Cells exhibit dramatic shifts in mitochondrial behavior during stress, development, neuronal activity, apoptosis, and disease. Our laboratory uses biochemical and genetic approaches to uncover the cellular pathways that modulate the activity of the mitochondrial fusion and fission complexes.