Changes in mitochondrial DNA in cardiac hypertrophy in the rat.

Abstract

SUMMARY We studied DNA (mtDNA) replication in adult female rat hearts undergoing hypertrophy secondary to constriction of the ascending aorta. MtDNA was measured in isolated mitochondria by a fiuorometric method adapted for that purpose. The conditions for removal of contaminating nuclear DNA were developed, and the purity of the mtDNA was assessed from its molecular conformation (open and closed circles) and by renaturation-kinetic analysis. The mtDNA concentration in mitochondria, expressed as micrograms of DNA per milligram of mitochondrial protein, increased 2, 4, and 7 days postoperatively by 21, 73, and 98%, respectively. Similar results were obtained when mtDNA was expressed per nanomole of cytochrome a. The population of replicative intermediates of mtDNA was analyzed by electron microscopy. In normal hearts, we observed molecular forms characteristic of animal mtDNA, such as circular monomers and dimers, catenated molecules, D-loops, expanded Dloops, and gapped molecules. D-loop frequency, which was near 50% in the mtDNA of control hearts, was markedly reduced to 5-7% in hypertrophying hearts. This result indicates that the increase in replicative flux of mtDNA is associated with the removal of a block in the conversion of D-loops to other intermediates. Ore Res. 46: 1979 IT is now well established that increased tension in the ventricular wall is correlated with increased metabolic activity of the heart. It is also known that the energy requirement of the myocardium is met completely by aerobic metabolism during both rest and strenuous activity (Neely and Morgan, 1974). This dependence of the myocardium on oxidative processes is reflected by the high content of mitochondria, which occupy 35% of the cardiac cell volume (Page et al., 1972).The increased requirement for ATP during acute work overload is met effectively by the respiratory control mechanism: the accumulating ADP stimulates oxidative phosphorylation. If the hemodynamic overload is sustained, however, the capacity of the existing contractile and energy-producing apparatus is exceeded, and a second adaptive process, cardiac growth, is activated. This adaptive growth is reflected in increased incorporation of labeled amino acids into cardiac subcellular fractions, including mitochondria, as measured both in vivo (Zak and Fischman, 1971) and in vitro (Shahab and Wollenberger, 1970). Quantitative electronmicroscopic analysis (Page et al., 1972) and measurements of mitochondrial cytochromes and respiratory enzymes (Albin et al., 1973) indicate that, in early hypertrophy, mitochondria accumulate in preference to other organelles. Thus, the study of processes leading to mitochondrial proliferation may provide clues about the still elusive feedback mechanism that couples hemodynamic load with biosynthetic pathways. In this respect, the report of Meerson and Pomoinitsky (1972) that the amount of mtDNA, expressed per unit of mitochondrial protein, is increased strikingly after aortic constriction in the rat is of great interest. The mtDNA concentra...

Effects of Aging on Mitochondrial DNA Copy Number and Cytochromec Oxidase Gene Expression in Rat Skeletal Muscle, Liver, and Heart

“…Previous studies have indeed shown that long term aerobic exercise in skeletal muscles may increase mitochondrial density in humans (14) as well as mitochondrial DNA content in animal models (18,26,27). Left ventricular hypertrophy is also a common feature of the aging myocardium in both humans and rodents (28), and experimentally induced hypertrophy increased cardiac mitochondrial DNA content in adult rats (29,30). Differential effects of aging on mitochondrial antioxidant defense systems should also be taken into account.…”

Endothelial cells maintain a reduced redox environment even as mitochondrial function declines

“…Hypertrophy has also been found to occur with age in the left ventricular myocardium of humans and rodents (31). Rat models of hypertrophy have shown that mitochondrial DNA content increases with an increase in cell size (43). It appears that age-related alterations in the mitochondrial genome number differ depending on the tissue, and variations with age may be related to cell size.…”

The Effects of Steroid Hormones on the Transcription of Genes Encoding Enzymes of Oxidative Phosphorylation

“…mitochondrial biogenesis, maximizes energy output. This is observed in chronic skeletal muscle stimulation in rat (Hood et al 1989) and rabbit (Williams, 1986) and in cardiac muscle of rats subjected to aortic occlusion (Rajamanickam et al 1979;Wiesner et al 1994), as well as during certain development periods, e.g. post-natally in liver and kidney (Djouadi et al 1996).…”