Development of new treatments for mitochondrial disease using curcumin

Mitochondrial disease affects 1 in 4,300 people resulting in significant morbidity and mortality for patients. A type of mitochondrial disease is Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke Like Episodes (MELAS). This disease is caused by a point mutation at the 3243 position where adenine is substituted to a guanine, encoding for the leucine tRNA. Currently there is no cure for mitochondrial disease. A proposed therapy for treating mitochondrial disease is through the use of curcumin and deoxyribonucleosides (dN’s) to stimulate mitochondrial biogenesis and restore mitochondrial functioning. In this thesis, the effects of curcumin, in combination with deoxyribonucleosides on mitochondrial biogenesis in cybrid cells containing ~90% of the m.3243A>G mutation associated with MELAS was examined. The combination treatment increased cell growth in the mutant cells but had no effect on mtDNA copy number. However, mtDNA copy number was increase in control and mutant cells following treatment with curcumin only. Steady-state levels of the OXPHOS protein subunits NDUFB8 (CI) and SDHA (CII) significantly increased in the mutant cells following curcumin treatment, however, other individual mitochondrial proteins were not altered. Steady-state levels of native complex V significantly decreased in mutant cells following curcumin treatment. No alterations were observed in the steady-state levels of native complex II following treatment with curcumin. Basal and maximal mitochondrial respiratory rates were also unaffected in both control and mutant cells following curcumin treatment. Overall, these findings highlight that the there is no additive affect of curcumin and dN’s combination on mitochondrial biogenesis and overall metabolic function. However, concentrations of curcumin and dN’s could be further optimised, which would allow their potential development into therapies for treating mitochondrial diseases.