Mitochondria play a central role in cellular metabolism. They produce ATP from numerous fuel sources and participate in many biochemical pathways, such as amino acid metabolism, Fe-S cluster assembly, and calcium handling. Mitochondria also exhibit interesting macroscopic behaviors, including fusion (joining of two organelles into one), fission (division), active transport along cytoskeletal elements, and mitophagy (targeted destruction). Together, these behaviors are known as mitochondrial dynamics.

On the surface, mitochondrial behaviors are functionally independent from their biochemical roles and mediated by distinct proteins. However, recent data from our lab and others suggest metabolism influences mitochondrial behavior and vice versa. For instance, culture conditions that enhance the oxidative phosphorylation activity of mitochondria serve to increase fusion rates (Cell Metabolism 19, 630-41, 2014) and increase mitophagy rates (Cell Metabolism 17, 719-30, 2013). Conversely, genetic ablation of mitochondrial fusion results in severe OXPHOS defects (Journal of Biological Chemistry 280, 26185-92, 2005).

Muscle dysfunction and weakness are common symptoms of mitochondrial diseases caused by mutations within the mitochondrial genome (mtDNA). In comparison with other myopathies, mitochondrial myopathies have some distinct features. In particular, individual muscle fibers are affected in a regional manner, with affected segments surrounded by normal regions of the fiber (see right). Affected regions are classified by a loss of mitochondrial activity and an accumulation of mutant mitochondria. Interestingly, the mutation does not spread beyond the affected region, which suggests that mechanisms are in place to restrict the defect from disrupting the whole fiber.

We have recently developed methods to quantify mitochondrial regionalization within muscle fibers (Cell Metabolism 22, 1033-44, 2015). Satellite cells are muscle-resident stem cells that incorporate into existing myofibers. Using a satellite-cell specific promoter, we have stochastically activated individual myonuclei in live animals to label mitochondria in their immediate vicinity. The spread of the mitochondrial signal provides a relative measure of the extent of regionalization, which we term a mitochondrial “domain.” We have found the type of muscle fiber, as well as the extent of mitochondrial fusion occurring in that fiber, determines domain size. Indeed, mitochondrial fusion appears to promote spreading of the activated signal, thereby extending the length of the domain.