Abstract

The relationship between genotype and phenotype in mitochondrial diseases is complicated and poorly understood. The clinical manifestations of mitochondrial diseases vary dramatically in terms of symptoms, severity and age of onset. Furthermore, the same genetic defect can result in different symptoms amongst various individuals whereas different mutations can lead to the same phenotype. Such variation makes it impossible to predict the phenotypes of mitochondrial disease based on genetic defects. Since mitochondria are crucial for energy supply, it has traditionally been accepted that ATP depletion is the main contributing factor to the symptoms associated with mitochondrial diseases. However, as mitochondria participate in such a diverse range of cellular functions and since the phenotypes of mitochondrial disease are extremely variable, the pathology of human mitochondrial diseases may be due to alterations in any of the various mitochondrial functions. For example, the tissue dysfunction associated with specific mitochondrial diseases may be due to excessive ROS production, altered calcium homeostasis which stimulates apoptosis or, as recent work has shown, activation of stress-sensitive signalling pathways. This review highlights these various mechanisms implicated in the cytopathology of mitochondrial disease and dysfunction.

Keywords: Mitochondrial disease, pathogenic mechanisms, ROS, ageing, calcium signalling, AMPK