Abstract
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.
Highlights
Individuals are frequently affected by age-related symptoms and diseases such as higher susceptibility towards infections, higher incidence of myelodysplastic syndrome (MDS) and leukemia [1]
Our results revealed that the presence of mitochondrial DNA (mtDNA) polymorphisms in the ND4, CYTB and COX3 genes are associated with decreasing intracellular reactive oxygen species (ROS) levels as well as decreasing lymphocyte counts during aging
During aging ROS and mitochondrial superoxide production significantly decreased in background strain C57BL/6Ntac (B6Ntac)
Summary
Individuals are frequently affected by age-related symptoms and diseases such as higher susceptibility towards infections, higher incidence of myelodysplastic syndrome (MDS) and leukemia [1]. Microenvironment and intrinsic factors were described to cause changes in hematopoietic stem cells (HSC) during aging, resulting in lineage skewing towards enhanced myelopoiesis, but impaired erythropoiesis and lymphopoiesis [2]. The major cellular source of ROS is the mitochondrial respiratory chain [3]. Elevated concentrations of ROS may damage various cell components [4,5,6]. Elevated concentrations of hydrogen peroxide (H2O2) were shown to play a crucial role as signaling molecules in different cellular processes. Antioxidants like thioredoxines or peroxiredoxins were www.impactjournals.com/oncotarget suggested to serve as ROS scavengers but to function as sensors and effectors influencing various processes as apoptosis and cell growth [7]
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