Popis: |
PhD (Biochemistry), North-West University, Potchefstroom Campus Mitochondrial diseases (MD), such as Leigh Syndrome (LS), present with severe neurological and muscular phenotypes in patients, but have no known cure and limited treatment options. Based on their neuroprotective effects against other neurodegenerative diseases in vivo and their positive impact as an antioxidant against complex I deficiency in vitro, we investigated the potential protective effect of metallothioneins (MT) in a whole-body Ndufs4 (complex I) knockout mouse model (with a very similar phenotype to LS) crossed with an Mt1 overexpressing mouse model (TgMt1). Despite subtle reductions in the expression of neuroinflammatory markers GFAP and IBA1 in the vestibular nucleus and hippocampus, no improvement was observed in survival, growth, locomotor activity, balance or motor coordination in the Mt1 overexpressing Ndufs4-/- mice. Furthermore, at a cellular level, no differences were detected in the metabolomics profile, enzyme activity or protein oxidation levels in the brain and quadriceps from these mice. These outcomes, together with linked studies showed no differences in the expression of selected one-carbon (1C) metabolism and oxidative stress metabolism genes in the brain and quadriceps, nor in the ROS levels of macrophages derived from these mice. Therefore, we conclude that MT1 overexpression does not protect against the impaired motor activity or improve survival in these complex I deficient mice. The unexpected absence of increased oxidative stress and metabolic redox imbalance in this MD model may explain these observations. However, tissue-specific observations such as the mildly reduced inflammation in the hippocampus and vestibular nucleus, as well as differential MT1 expression in these tissues, may yet reveal a tissue-specific role for MT1 or other MT isoforms (MT2 and MT3) in these mice. Doctoral |