ABSTRACT
BACKGROUND: Mitochondrial DNA (mtDNA) encodes for the respiratory chain proteins. Genetic alterations in mtDNA have been described during aging and linked to impaired hematopoiesis. MATERIALS AND METHODS: We investigated two novel conplastic mouse strains harboring a mitochondrial nt7778 G/T polymorphism leading to an amino acid exchange in respiratory chain complex V. Effects on reactive oxygen species (ROS) and adenosine triphosphate (ATP) levels, as well as bone marrow composition and peripheral blood counts, were investigated during aging (up to 24 month). RESULTS: The polymorphism correlated with significantly decreased ROS levels in aged mice. Effects on hematopoiesis were marginal and not statistically significant: numbers of erythroid cells in bone marrow, as well as mean corpuscular hemoglobin, tended to decrease over time. CONCLUSION: The investigated polymorphism is associated with decreased ROS levels in aged hematopoietic cells but does not significantly influence hematopoiesis itself.
Subject(s)
Cellular Senescence/genetics , DNA, Mitochondrial/genetics , Hematopoietic Stem Cells/metabolism , Mitochondrial Proton-Translocating ATPases/genetics , Polymorphism, Single Nucleotide , Reactive Oxygen Species/metabolism , Adenosine Triphosphate/metabolism , Aging/genetics , Animals , Cells, Cultured , Erythroid Cells/cytology , Erythroid Cells/metabolism , Hematopoiesis/genetics , Hematopoietic Stem Cells/cytology , Hemoglobins/metabolism , Mice, Inbred AKR , Mice, Inbred C57BL , Mice, Inbred Strains , Mitochondrial Proton-Translocating ATPases/metabolism , Species SpecificityABSTRACT
During aging, mitochondrial DNA (mtDNA) can accumulate mutations leading to increasing levels of reactive oxygen species (ROS). Increased ROS were described to activate formerly quiescent hematopoietic stem cells (HSC). Mutations in mtDNA were shown to enhance the risk for myelodysplastic syndrome and leukemia. However, the complex relationship between mtDNA variations, ROS and aging of the hematopoietic system is not fully understood.Herein, three mouse strains with mtDNA polymorphisms in genes of respiratory chain complexes I (ND4), III (CYTB) and IV (COX3) were compared to a reference strain during aging. Analysis focused on ROS and ATP levels, bone marrow composition and blood counts. Additionally, hematopoietic restoration capacity following cytotoxic stress was tested.Mice with polymorphisms in ND4 and CYTB gene had significantly decreasing ROS levels in bone marrow cells during aging, without effecting ATP levels. In addition, the frequency of stem and progenitor cells increased during aging but the amount of lymphocytes in the peripheral blood decreased during aging.In summary, the presence of mtDNA polymorphisms affecting the respiratory chain complexes I, III and IV was associated with altered ROS levels as well as changes in BM and peripheral blood composition during aging.
Subject(s)
Aging/genetics , Electron Transport Complex III/genetics , Genes, Mitochondrial , Hematopoiesis/genetics , NADH Dehydrogenase/genetics , Polymorphism, Genetic , Prostaglandin-Endoperoxide Synthases/genetics , Adenosine Triphosphate/metabolism , Age Factors , Aging/metabolism , Animals , Blood Cell Count , Bone Marrow Cells/metabolism , Female , Gene Knockout Techniques , Mice , Oxidative Stress , Reactive Oxygen Species/metabolismABSTRACT
Progress of age-related hematopoietic diseases such as myelodysplastic syndrome has previously been linked to enhanced levels of reactive oxygen species (ROS). Uncoupling protein 2 (UCP2) was found to reduce mitochondrial ROS production through uncoupling of the respiratory chain. The impact of UCP2 loss and elevated ROS on hematopoiesis during aging has not yet been investigated. In this study, UCP2 knockout mice were analyzed at aging stages of 3, 12, and 24 months with respect to oxidative and energy status of bone marrow cells. Further, the cellular bone marrow subpopulation composition was characterized, as were the differential blood counts at all time points. UCP2 knockout mice revealed enhanced levels of mitochondrial superoxide in elderly animals. Following oxidative stress, adenosine triphosphate (ATP) levels decreased more in the knockout mice than in the wild type. Investigation of bone marrow and blood counts of the knockout mice revealed an enhanced amount of monocytes and neutrophils, as well as a decreased amount of B cells and impaired erythropoiesis throughout aging. In summary, UCP2 induces protective effects on ROS and ATP levels during aging. Additionally, the results suggest an imbalance in hematopoiesis because of the lack of UCP2.
