Tissue distribution and disease manifestations of the tRNALys A»G(8344) mitochondrial DNA mutation in a case of myoclonus epilepsy and ragged red fibres

This man with myoclonus epilepsy and ragged red fibres (MERRF) syndrome due to the tRNA^Lys A»G⁽⁸³⁴⁴⁾ mutation of mitochondrial DNA (mtDNA) died of bronchopneumonia at 18 years of age. He had progressive clinical symptoms from 6 months of age manifesting as ataxia, myoclonic seizures, and muscle weakness. A postmortem examination revealed 91–99% mutated mtDNA in all 32 examined tissue samples, including various organs and different brain regions. The brain appeared without macroscopic changes, but microscopic examination showed degeneration with loss of nerve cells and gliosis affecting the globus pallidus, substantia nigra, red nucleus, dentate nucleus, inferior olivary nucleus, cerebellar cortex, and the spinal cord. Skeletal muscle showed cytochrome c oxidase deficient muscle fibres with proliferation of mitochondria. In addition to pathological changes of muscle and brain there were few morphological changes that could be attributed to his mitochondrial disease. These data support the concept that in patients with the tRNA^Lys A»G⁽⁸³⁴⁴⁾ mutation who are manifesting disease there are high levels of mutated mtDNA in all tissues, but only some tissues and brain regions are vulnerable.     

Locating ICT's benefits in elderly care

The impact of information and communication technology (ICT) is indirect and depends on redesign of practices and structures also outside health care. Improvements will only be realized if all parties involved can coordinate their efforts to take advantage of new technology. A 'package' of changed work practices and structures extending across organizational boundaries needs to be designed and implemented. This is very different from the common conception of introducing new ICT tools. Calls for 'evaluation of benefits' before new ICT systems are introduced need to recognize this complexity. This article investigates how analysis and economic evaluations can be used to improve decision-making when new applications are proposed. This is done by drawing parallels with experiences from other industries. We conclude that the entire 'change package' should be analysed for its consequences on the well-being of care recipients, and the requirements it presents for capital investments and changed labour inputs, in particular changed competence needs. Some concepts and structures are suggested for such evaluations.     

Sequence-specific stalling of DNA polymerase γ and the effects of mutations causing progressive ophthalmoplegia

A large number of mutations in the gene encoding the catalytic subunit of mitochondrial DNA polymerase γ (POLγA) cause human disease. The Y955C mutation is common and leads to a dominant disease with progressive external ophthalmoplegia and other symptoms. The biochemical effect of the Y955C mutation has been extensively studied and it has been reported to lower enzyme processivity due to decreased capacity to utilize dNTPs. However, it is unclear why this biochemical defect leads to a dominant disease. Consistent with previous reports, we show here that the POLγA:Y955C enzyme only synthesizes short DNA products at dNTP concentrations that are sufficient for proper function of wild-type POLγA. In addition, we find that this phenotype is overcome by increasing the dNTP concentration, e.g. dATP. At low dATP concentrations, the POLγA:Y955C enzyme stalls at dATP insertion sites and instead enters a polymerase/exonuclease idling mode. The POLγA:Y955C enzyme will compete with wild-type POLγA for primer utilization, and this will result in a heterogeneous population of short and long DNA replication products. In addition, there is a possibility that POLγA:Y955C is recruited to nicks of mtDNA and there enters an idling mode preventing ligation. Our results provide a novel explanation for the dominant mtDNA replication phenotypes seen in patients harboring the Y955C mutation, including the existence of site-specific stalling. Our data may also explain why mutations that disturb dATP pools can be especially deleterious for mtDNA synthesis.     

From the Cover: Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo

Mitochondrial dysfunction is heavily implicated in Parkinson disease (PD) as exemplified by the finding of an increased frequency of respiratory chain-deficient dopamine (DA) neurons in affected patients. An inherited form of PD is caused by impaired function of Parkin, an E3 ubiquitin ligase reported to translocate to defective mitochondria in vitro to facilitate their clearance. We have developed a reporter mouse to assess mitochondrial morphology in DA neurons in vivo and show here that respiratory chain deficiency leads to fragmentation of the mitochondrial network and to the formation of large cytoplasmic bodies derived from mitochondria. Surprisingly, the dysfunctional mitochondria do not recruit Parkin in vivo, and neither the clearance of defective mitochondria nor the neurodegeneration phenotype is affected by the absence of Parkin. We also show that anterograde axonal transport of mitochondria is impaired in respiratory chain-deficient DA neurons, leading to a decreased supply of mitochondria to the axonal terminals.