Wednesday, 13 May 2015

Mosaic Deficiency in Mitochondrial Oxidative Metabolism Promotes Cardiac Arrhythmia during Aging

http://www.sciencedirect.com/science/article/pii/S1550413115001606

Olivier R. Baris, Stefan Ederer, Johannes F.G. Neuhaus, Jürgen-Christoph von Kleist-Retzow, Claudia M. Wunderlich, Martin Pal, F. Thomas Wunderlich, Viktoriya Peeva, Gabor Zsurka, Wolfram S. Kunz, Tilman Hickethier, Alexander C. Bunck, Florian Stöckigt, Jan W. Schrickel, Rudolf J. Wiesner

It has previously been observed that, during aging, tissues can accumulate a small number of cells with high levels of mutated mitochondrial DNA (mtDNA). It was previously unknown whether mosaic mitochondrial deficiency was able to cause disease. Here, the authors investigate whether mosaicisim causes an age-related degeneration of heart tissue, in vivo.

To do this, the authors generated a mouse model which has a dominant-negative mutant of the mitochondrial replicative helicase Twinkle. The mice are engineered such that the mutant form of Twinkle is only active in myocardium. The result is an accelerated accumulation of mtDNA deletion mutations in the heart (10.92%+/-9.5% mutant load at 18 months), which replicates a decades-long process during human aging. By staining heart muscle for Complex IV (COX), the authors found a mosaic pattern of COX-negative cells by 18 months (0.56%+/-0.34% of cells by 18-months), whereas control mice showed none. COX-negative cells also showed a compensatory increase in mtDNA copy number, by around a factor of ~4.

As a result, the mutant mice were ~x8 more susceptible to spontaneous ventricular premature contractions at rest, and ~x3 more susceptible to atrioventricular blocks (loss of conductivity between the atria and ventricles of the heart) during stress. By analysing heart homogenate, the authors show that there is little difference between the enzyme activity between the control and mutant, across the whole tissue. This demonstrates that mosaicism causes a heart defect in these mice, not a general mitochondrial defect.


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