In vivo levels of mitochondrial hydrogen peroxide increase with age in mtDNA mutator mice
Angela Logan1, Irina G Shabalina, Tracy A Prime
1MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Cambridge, CB2 0XY, UK.
Abstract:
In mtDNA mutator mice, mtDNA mutations accumulate leading to a rapidly aging phenotype. However, there is little evidence of oxidative damage to tissues, and when analyzed ex vivo, no change in production of the reactive oxygen species (ROS) superoxide and hydrogen peroxide by mitochondria has been reported, undermining the mitochondrial oxidative damage theory of aging. Paradoxically, interventions that decrease mitochondrial ROS levels in vivo delay onset of aging. To reconcile these findings, we used the mitochondria-targeted mass spectrometry probe MitoB to measure hydrogen peroxide within mitochondria of living mice. Mitochondrial hydrogen peroxide was the same in young mutator and control mice, but as the mutator mice aged, hydrogen peroxide increased. This suggests that the prolonged presence of mtDNA mutations in vivo increases hydrogen peroxide that contributes to an accelerated aging phenotype, perhaps through the activation of pro-apoptotic and pro-inflammatory redox signaling pathways.
Insights
Mitochondrial DNA mutations accelerate aging by increasing mitochondrial hydrogen peroxide, not by causing immediate oxidative damage. This finding reconciles conflicting theories on aging and reactive oxygen species.
Area of Science:
- Mitochondrial biology
- Aging research
- Genetics
Background:
- Mitochondrial DNA (mtDNA) mutations are linked to accelerated aging.
- The role of mitochondrial reactive oxygen species (ROS) in aging is debated due to conflicting evidence.
- Existing studies show no immediate increase in ROS production from mitochondria with mtDNA mutations.
Purpose of the Study:
- To investigate the in vivo levels of mitochondrial hydrogen peroxide in aging mice with mtDNA mutations.
- To reconcile the observed aging phenotype with existing theories on mitochondrial oxidative stress.
Main Methods:
- Utilized a mitochondria-targeted mass spectrometry probe (MitoB) to measure hydrogen peroxide within mitochondria of living mice.
- Compared hydrogen peroxide levels in young and aging mtDNA mutator mice versus control mice.
Main Results:
- Mitochondrial hydrogen peroxide levels were similar in young mutator and control mice.
- Hydrogen peroxide levels increased in mutator mice as they aged.
- This increase suggests a delayed effect of mtDNA mutations on mitochondrial ROS.
Conclusions:
- Prolonged mtDNA mutations in vivo lead to increased mitochondrial hydrogen peroxide, contributing to accelerated aging.
- This mechanism may involve the activation of pro-apoptotic and pro-inflammatory redox signaling pathways.
- The findings support a revised understanding of the mitochondrial oxidative damage theory of aging.
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