Dysfunctioning of human mitochondria is found in a rapidly increasing number of patients. The mitochondrial system for energy transduction is very vulnerable to damage by genetic and environmental factors. A primary mitochondrial disease is caused by a genetic defect in a mitochondrial enzyme or translocator. More than 60 mitochondrial enzyme deficiencies have been reported. Secondary mitochondrial defects are caused by lack of compounds to enable a proper mitochondrial function or by inhibition of that function. This may result from malnutrition, circulatory or hormonal disturbances, viral infection, poisoning, or an extramitochondrial error of metabolism. Once mitochondrial ATP synthesis decreases, secondary mitochondrial lesions may be generated further, due to changes in synthesis and degradation of mitochondrial phospholipids and proteins, to mitochondrial antibody formation following massive degradation, to accumulation of toxic products as excess acyl-CoA, to the depletion of Krebs cycle intermediates, and to the increase of free radical formation and lipid peroxidation.

We have recently diagnosed a patient with anaemia, severe tubulopathy, and diabetes mellitus. As the clinical characteristics resembled Pearson marrow-pancreas syndrome, despite the absence of malfunctioning of the exocrine pancreas in this patient, we have performed DNA analysis to seek for deletions in mtDNA. DNA analysis showed a novel heteroplasmic deletion in mtDNA of 8034bp in length, with high proportions of deleted mtDNA in leukocytes, liver, kidney, and muscle. No deletion could be detected in mtDNA of leukocytes from her mother and young brother, indicating the sporadic occurrence of this deletion. During culture, skin fibroblasts exhibited a rapid decrease of heteroplasmy indicating a selection against the deletion in proliferating cells. We estimate that per cell division heteroplasmy levels decrease by 0.8%. By techniques of fluorescent in situ hybridisation (FISH) and mitochondria-mediated transformation of 0 cells we could show inter-as well as intracellular variation in the distribution of deleted mtDNA in a cell population of cultured skin fibroblasts. Furthermore, we studied the mitochondrial translation capacity in cybrid cells containing various proportions of deleted mtDNA. This result revealed a sharp threshold, around 80%, in the proportion of deleted mtDNA, above which there was strong depression of overall mitochondrial translation, and below which there was complementation of the deleted mtDNA by the wild-type DNA. Moreover, catastrophic loss of mtDNA occurred in cybrid cells containing 80% deleted mtDNA.