MECHANISMS OF TOXICITY IN MITOCHONDRIAL DISEASE

Objective: The most frequently encountered CNS damage in mitochondrial diseases is the presence of lesions revealed by MRI or CT in areas of the basal ganglia. Neuronal cell death in these areas (Leigh Disease) occurs, likely due to a combination of events resulting from inability to generate energy oxidatively. These include loss of energy charge, accumulation of hydrogen ions, increases in free Ca++ and increases in reactive oxygen species.

Methods and Results: Analysis of MtDNA based disorders were used to compare what is known about metabolic control and generation of ATP in model systems. Comparison of threshold effects imposed by heteroplasmy give some insight into the plasticity of energy production systems. Comparison of the constraints imposed by various defects in the pyruvate dehydrogenase complex is also instructive in that relatively small changes are known to produce major sequelae with local biochemical consequences. The interruption of electron transport at complex I is especially prone to abnormalities in oxygen-free radical generation. Response to excessive superoxide generation by elevation of MnSOD is one of the defence mechanisms that can be employed to reduce such free radical effects. Recent generation of transgenic mice expressing modified DNA polymerase gamma have also shown that MtDNA mutation can have profound effects on the ageing process. Gene defects affecting mitochondrial fission, fusion and movement are also adding to the overall picture that many aspects of mitochondrial function are essential to the well-being of the CNS.

Conclusion: This analysis of factors affecting mitochondrial energy metabolism and sequelae leading to cell death should lead to a better understanding of how we might focus our efforts to intervene in the neurodegenerative process.