Polymorphisms of the murine mitochondrial ND4, CYTB and COX3 genes impact hematopoiesis during aging

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// Christin Kretzschmar 1,* , Catrin Roolf 1,* , Katrin Timmer 1 , Anett Sekora 1 , Gudrun Knübel 1 , Hugo Murua Escobar 1 , Georg Fuellen 2 , Saleh M. Ibrahim 3 , Markus Tiedge 4 , Simone Baltrusch 4 , Robert Jaster 5 , Rüdiger Köhling 6 and Christian Junghanss 1 1 Department of Medicine III - Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany 2 Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany 3 Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany 4 Institute of Medical Biochemistry and Molecular Biology, Rostock University Medical Center, Rostock, Germany 5 Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany 6 Oscar Langendorff Institute of Physiology, Rostock University Medical Center, Rostock, Germany * These authors have equally contributed to this work Correspondence to: Christian Junghanss, email: // Keywords : mtDNA, aging, hematopoiesis, ROS, stem cell, Gerotarget Received : December 15, 2015 Accepted : September 02, 2016 Published : September 10, 2016 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.