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Abstract
Adult human heart mitochondrial DNA (mtDNA) has recently been shown to have a complex organization with abundant dimeric molecules, branched structures and four-way junctions. In order to understand the physiological significance of the heart-specific mtDNA maintenance mode and to find conditions that modify human heart mtDNA structure and replication, we analyzed healthy human heart of various ages as well as several different heart diseases, including ischemic heart disease, dilated as well as hypertrophic cardiomyopathies, and several mitochondrial disorders. By using one- and two-dimensional agarose gel electrophoresis, various enzymatic treatments and quantitative PCR we found that in human newborns heart mtDNA has a simple organization, lacking junctional forms and dimers. The adult-type branched forms are acquired in the early childhood, correlating with an increase in mtDNA copy number. Mitochondrial disorders involving either mutations in the mtDNA polymerase γ (PolGα) or mtDNA helicase Twinkle, while having no obvious cardiac manifestation, show distinct mtDNA maintenance phenotypes, which are not seen in various types of diseased heart or in mitochondrial disorders caused by point mutations or large-scale deletions of mtDNA. The findings suggest a link between cardiac muscle development, mtDNA copy number, replication mode and topological organization. Additionally, we show that Twinkle might have a direct role in the maintenance of four-way junctions in human heart mtDNA.
Highlights
The heart is the most energy demanding tissue in the human body consuming 0.1 ml O2/g per minute – an amount that is only surpassed by insect flight muscles [1]
A mutation in the catalytic subumit of DNA polymerase c (PolGa;p.-G848S/p-S1104C) mutation influenced only the maintenance of dimeric mitochondrial genomes in adult human heart. These results suggest that Twinkle is directly involved in the maintenance of mitochondrial DNA (mtDNA) recombination in adult human heart
When analyzing the age dependency of junctional mtDNA forms in healthy humans, we noticed that notably less mtDNA replication intermediates (mtRIs) existed in newborns and that four-way junctional mtDNA molecules – a feature typical to adult heart – were undetectable (Figure 1)
Summary
The heart is the most energy demanding tissue in the human body consuming 0.1 ml O2/g per minute – an amount that is only surpassed by insect flight muscles [1]. Heart has an impressive reserve capacity; human cardiac muscle oxygen consumption can rise four-fold without any effect on the steady-state ATP levels. The importance of oxidative metabolism is highlighted by the high mitochondrial content of heart muscle cells, where up to 40% of the cellular volume can consist of mitochondria. The few studies including adult human cardiac muscle propose a mean copy number of 69706920 to 923565457 mtDNA per cell, with individual numbers ranging from 4 000 to up to 34 000 [3,4]. Skeletal muscle cells, depending on the muscle, have copy numbers ranging from 1000 to 4000 mtDNA molecules per cell
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