Human Molecular Genetics Advance Access originally published online on February 1, 2008
Human Molecular Genetics 2008 17(10):1418-1426; doi:10.1093/hmg/ddn030
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Age-associated mosaic respiratory chain deficiency causes trans-neuronal degeneration
,
1 Department of Laboratory Medicine 2 Department of Neuroscience 3 Department of Cell and Molecular Biology, Karolinska Institutet, S-17177 Stockholm, Sweden
* To whom correspondence should be addressed at: Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, 14186 Huddinge, Stockholm, Sweden. Tel: +46 858583724; Fax: +46 87795383; Email: nils-goran.larsson{at}ki.se
Received December 10, 2007; Accepted January 27, 2008
Heteroplasmic mitochondrial DNA (mtDNA) mutations (mutations present only in a subset of cellular mtDNA copies) arise de novo during the normal ageing process or may be maternally inherited in pedigrees with mitochondrial disease syndromes. A pathogenic mtDNA mutation causes respiratory chain deficiency only if the fraction of mutated mtDNA exceeds a certain threshold level. These mutations often undergo apparently random mitotic segregation and the levels of normal and mutated mtDNA can vary considerably between cells of the same tissue. In human ageing, segregation of somatic mtDNA mutations leads to mosaic respiratory chain deficiency in a variety of tissues, such as brain, heart and skeletal muscle. A similar pattern of mutation segregation with mosaic respiratory chain deficiency is seen in patients with mitochondrial disease syndromes caused by inherited pathogenic mtDNA mutations. We have experimentally addressed the role of mosaic respiratory chain deficiency in ageing and mitochondrial disease by creating mouse chimeras with a mixture of normal and respiratory chain-deficient neurons in cerebral cortex. We report here that a low proportion (>20%) of respiratory chain-deficient neurons in the forebrain are sufficient to cause symptoms, whereas premature death of the animal occurs only if the proportion is high (>60–80%). The presence of neurons with normal respiratory chain function does not only prevent mortality but also delays the age at which onset of disease symptoms occur. Unexpectedly, respiratory chain-deficient neurons have adverse effect on normal adjacent neurons and induce trans-neuronal degeneration. In summary, our study defines the minimal threshold level of respiratory chain-deficient neurons needed to cause symptoms and also demonstrate that neurons with normal respiratory chain function ameliorate disease progression. Finally, we show that respiratory chain-deficient neurons induce death of normal neurons by a trans-neuronal degeneration mechanism. These findings provide novel insights into the pathogenesis of mosaic respiratory chain deficiency in ageing and mitochondrial disease.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
Present address: Institute of Medical Technology and Tampere University Hospital, FI-33014 University of Tampere, Finland.