Deletion-Mutant mtDNA Increases in Somatic Tissues but Decreases in Female Germ Cells With Age

Abstract

Abstract The proportions of mutant and wild-type mtDNA are crucial in determining the severity of mitochondrial diseases. It has been generally considered that deletion-mutant mtDNA has replication advantages and accumulates with time. Here, we examine the tissue-by-tissue proportions of mutant mtDNA with a 4696-bp deletion (ΔmtDNA) and wild-type mtDNA in mitochondrial disease model mice (mito-mice). Comparison of the proportions of ΔmtDNA in each tissue at various ages showed that the rate of accumulation of ΔmtDNA differed among tissues. The heart, skeletal muscles, kidney, liver, testis, and ovary showed increases in the proportion of ΔmtDNA with age, but the pancreas, spleen, brain, and blood showed only a slight or no increase in proportion. In contrast to the somatic tissues, however, the germ cells of female mito-mice and resultant offspring showed a strong decrease in ΔmtDNA with maternal age. The decrease was so acute that some offspring showed complete disappearance of ΔmtDNA, even though their elder brothers and sisters had high proportions of ΔmtDNA. Female germ cells have a machinery that prevents the inheritence of defective mtDNA to the following generation since germ cells are kept for a long time until they are ovulated.