Consequences of mtDNA Mutations

In the past decade, a variety of mtDNA mutations have been reported to have pathogenic roles underlying a range of mitochondrial diseases (Ml5). However, aside from biochemical defects in respiration, the molecular consequences of these mtDNA mutations remain poorly understood. Recently, the consequences of several mtDNA mutations have been extensively studied at the molecular and the cellular levels. 

Several studies revealed that the A3243G mutation is associated with the decrease in protein synthesis of affected cells (Cl 1, S5). When the ratio of mutant 

Biochemical Basis for How mtDNA Mutations Cause Mitochondrial Dysfunction 

Deficient respiratory chain function caused by mtDNA mutations could affect various biochemical functions of mitochondria, such as mitochondrial membrane potential, ATP synthesis, ATP/ADP ratio, ROS production, and calcium homeostasis (S14). 

On the other hand, defective respiratory function elicited by the mtDNA mutation contributes to an increase in the production of ROS and free radicals, thereby causing higher oxidative stress and severe oxidative damage in affected cells (P2, W6). Because either enhanced oxidative stress or disruption of calcium homeostasis is an important factor in the triggering of cell death, mitochondrial dysfunction in tissue cells from MELAS and MERRF patients may contribute significantly to the pathogenesis of these diseases. 

---