Mitochondrial Myopathies
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 (Mishra et al., Cell Metabolism 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 (see below). 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.
We therefore hypothesize that fusion rates play a role in determining the progression of mitochondrial disease. Using mouse models of disease in combination with conditional knockout alleles for pro-fusion proteins (mitofusin 1 and 2), we will test this hypothesis. Data from these studies will suggest whether modulation of organellar dynamics may be beneficial in the treatment of mitochondrial diseases.
