In the range of this project we are performing complex characterization of mitochondrial respiratory chain function and the related parameters responsible for or involved in mitochondrial defect-mediated cellular dysfunction. Our studies underline an important role of the oxidative stress in the pathogenesis of some of the mitochondrial disorders caused by mutations in nuclear or mitochondrial DNA. Our studies with the usage of primary fibroblast cultures derived from patients (harbouring mutations in mtDNA and nDNA, which were identified to be responsible for mitochondrial defects) indicate a direct correlation between the profile of altered mitochondrial parameters, reactive oxygen species (ROS) production, status of the antioxidant defence system and type and mechanism of the mitochondrial defect. In other words, a defect in a particular complex of the mitochondrial respiratory chain can be described according to the characteristic pattern of the investigated parameters (bioenergetics, ROS production, and antioxidant enzyme levels). Such methodical approach has been also extremely helpful to study mitochondrial dysfunction in the skin fibroblasts of patients with Huntington's disease. We were able to visualise differences in the bioenergetic profile and in the production of reactive oxygen species between healthy people's fibroblasts and the skin fibroblasts of patients with Huntington's disease. We have also shown that the changes in the obtained profile are related to the stage of the disease. Moreover, depending on mitochondrial defect, the reduction of oxidative stress in the examined patients fibroblasts resulted in an improvement of the mitochondrial parameters.
Interestingly, our studies conducted with the use of patient’s fibroblasts, allowed us to prove that intracellular oxidative stress as a cause of mitochondrial dysfunction also takes a part in the activation of the pro-oxidative p66Shc pathway. We assumed that in the case of cellular response to the intracellular oxidative stress we can observe something like “vicious cycle” of reactive oxygen species production.
