Mitochondrial DNA alterations and reduced mitochondrial function in aging

Abstract

Oxidative damage to mitochondrial DNA increases with aging. This damage has the potential to affect mitochondrial DNA replication and transcription which could alter the abundance or functionality of mitochondrial proteins. This review describes mitochondrial DNA alterations and changes in mitochondrial function that occur with aging. Age-related alterations in mitochondrial DNA as a possible contributor to the reduction in mitochondrial function are discussed.

Figure 1

Effects of aging on mitochondrial DNA content in gastrocnemius medial, gastrocnemius lateral, soleus, liver, and heart tissues of rats. Bars represent average ± S.E. of values from seven young (6 months) and nine old (27 months) animals. Under each bar are shown representative bands from Southern blots from two animals of each age group. Top bands show signals from the mtDNA fragment (3.0 kilobases), and bottom bands show signals from the nuclear DNA fragment containing the 28 S rRNA gene (6.4 kilobases). *, statistically different results (p < 0.03 or less) using Student's t test for unpaired data comparing young and old rats. This research was originally published in The Journal of Biological Chemistry. Barazzoni, R., Short, K. R. and Nair, K. S. Effects of aging on mitochondrial DNA copy number and cytochrome c oxidase gene expression in rat skeletal muscle, liver, and heart. J Biol Chem. 2000; 275:3343-7. © the American Society for Biochemistry and Molecular Biology.

Figure 2

Decline in muscle mtDNA abundance and mitochondrial ATP production rate with age. (A) mtDNA abundance was measured using a quantitative real-time PCR approach with a probe to the NADH Dehydrogenase 1 gene and is expressed in arbitrary units (AU). (B) Mitochondrial ATP production rate is shown using glutamate plus malate as a substrate. Taken with permission from Short et al., 2005a.

Figure 3

Protein synthesis rates and content of muscle mitochondrial proteins. Fractional synthesis rates (FSR) of skeletal muscle mitochondrial protein using plasma [13C]KIC (A) and tissue fluid [13C]leucine (B) as precursor pool enrichment, and as a percentage of mixed protein synthesis rates (C) in young, middle-aged, and old human subjects. *, P < 0.05; **, P < 0.01 versus young. (D) Relative abundance of mitochondrial proteins in muscle from young and older subjects. The percentage difference (*, P < 0.05) of older relative to young is shown. Negative values indicate less protein in older subjects. Taken with permission from Rooyackers et al., 1996 and Short et al., 2005a.

Figure 4

Mitochondrial DNA damage accumulates with aging. Damaged DNA may impair mitochondrial DNA replication and/or induce mitochondrial DNA degradation, both of which could result in a decline in levels of mitochondrial DNA, mRNA, and protein. Reduced levels of mitochondrial proteins could result in decreased ATP synthesis and an eventual decline in physical function.