Multiple sclerosis is likely caused by a complex interaction of multiple genes and environmental factors. The contribution of mitochondrial DNA genetic backgrounds has been frequently reported. To evaluate the effect of mitochondrial DNA haplogroups in the same genetic and environmental circumstances, we have built human transmitochondrial cell lines and simulated the effect of axon demyelination, one of the hallmarks of multiple sclerosis pathology, by altering the ionic gradients through the plasmalemma (membrane) and increasing ATP consumption. In this model, mitochondrial biogenesis is observed. This process is larger in Uk cybrids, which mirrors their lower oxidative phosphorylation capacity in basal conditions. This model replicates a process occurring in both MS patients suffering from multiple sclerosis and several animal models of axon demyelination. Therefore, it can be used to analyze the contribution of various mitochondrial DNA genotypes to multiple sclerosis. In this sense, a longer or stronger energy stress, such as that associated with demyelinated axons in multiple sclerosis, could make Uk individuals more susceptible to this pathology. Finally, pharmacologic compounds targeted to mitochondrial biogenesis could be a potential therapy for multiple sclerosis.
A cybrid (cytoplasmic hybrid) is a eukaryotic (Uk) cell (as opposed to prokaryotic found in bacteria) line produced by the fusion of a whole cell with a cytoplast. Cytoplasts are enucleated cells (cells minus a nucleus). This enucleation can be affected by simultaneous application of centrifugal force and treatment of the cell with an agent that disrupts the cytoskeleton. A cybrid is then a hybrid cell which combines the nuclear genome from one source with the mitochondrial genome from another source. Using this powerful tool, it is possible to dissociate the genetic contribution of the mitochondrial genome from that of the nuclear genome.
One problem associated with progression in MS is mitochondrial and energy problems. Could this be a new tool to study this and find new treatments to rectify the energy imbalance that occurs in cells during MS?