Burgin 2020 Int J Mol Sci
|Burgin HJ, Lopez Sanchez MIG, Smith CM, Trounce IA, McKenzie M (2020) Pioglitazone and deoxyribonucleoside combination treatment increases mitochondrial respiratory capacity in m.3243A>G MELAS cybrid cells. Int J Mol Sci 21:E2139.|
Abstract: The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that aim to stimulate mitochondrial biogenesis to boost ATP generation above a critical disease threshold. Here, we examine the effects of the peroxisome proliferator-activated receptor γ (PPARγ) activator pioglitazone (PioG), in combination with deoxyribonucleosides (dNs), on mitochondrial biogenesis in cybrid cells containing >90% of the m.3243A>G mutation associated with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). PioG + dNs combination treatment increased mtDNA copy number and mitochondrial mass in both control (CON) and m.3243A>G (MUT) cybrids, with no adverse effects on cell proliferation. PioG + dNs also increased mtDNA-encoded transcripts in CON cybrids, but had the opposite effect in MUT cybrids, reducing the already elevated transcript levels. Steady-state levels of mature oxidative phosphorylation (OXPHOS) protein complexes were increased by PioG + dNs treatment in CON cybrids, but were unchanged in MUT cybrids. However, treatment was able to significantly increase maximal mitochondrial oxygen consumption rates and cell respiratory control ratios in both CON and MUT cybrids. Overall, these findings highlight the ability of PioG + dNs to improve mitochondrial respiratory function in cybrid cells containing the m.3243A>G MELAS mutation, as well as their potential for development into novel therapies to treat mitochondrial disease.
• Keywords: MELAS, OXPHOS, Cybrid, Deoxyribonucleosides, Mitochondrial biogenesis, Mitochondrial disease, Oxidative phosphorylation, Pioglitazone • Bioblast editor: Plangger M • O2k-Network Lab: AU Melbourne Trounce IA, AU Clayton St John J
Labels: MiParea: Respiration, mt-Biogenesis;mt-density, mtDNA;mt-genetics, Pharmacology;toxicology
Stress:Mitochondrial disease Organism: Human Tissue;cell: Other cell lines Preparation: Intact cells
Coupling state: LEAK, ROUTINE, ET Pathway: ROX HRR: Oxygraph-2k