Mitochondrial integrity is impaired in MELAS patients (LB164)

Abstract

Mitochondrial diseases are disorders that can be caused by either mitochondrial or nuclear DNA mutations. One of the most prominently studied mitochondrial diseases is mitochondrial myopathy, encephalopathy, lactic acidosis and stroke‐like episodes (MELAS), caused by a mutation in the tRNA‐leucine gene within mtDNA. While the symptoms of this disease have been studied, the molecular manifestations of this mutation remain to be clearly understood. Since alterations in organelle function underlie the pathophysiology of various mitochondrial diseases, we explored mitochondrial morphology, cytochrome c oxidase activity, reactive oxygen species (ROS) production and mitochondrial membrane potential in patient (n=3) and control fibroblast cell lines (n=3). Cells transfected with Mito ds‐Red and visualized using confocal microscopy revealed an increase in mitochondrial fragmentation in cells from MELAS patients, compared to control, coincident with reduced cytochrome c oxidase activity, higher ROS production and a greater membrane potential. The increase in organelle fragmentation observed in MELAS cells led us to investigate the proteins which regulate mitochondrial fission (Fis1 and Drp1) and fusion (Opa1). Our data suggest that the increase in organelle fragmentation was due to a tendency for a higher expression of Fis1 in MELAS cells, suggesting that mtDNA mutations have consequences for the expression of nuclear‐encoded fission proteins, resulting in altered organelle morphology. Future work will investigate the use of fission protein inhibitors to ameliorate mitochondrial function in MELAS cells.Grant Funding Source: Supported by Mitacs and Panacea Global