AbstractsBiology & Animal Science

Somatic stem cell (SSC) dysfunction is a common feature of mouse models of premature ageing, most of which are created by disturbing nuclear DNA repair, damage recognition or ROS defence. The SSC dysfunction leads to decline in SSCs ability to maintain tissue homeostasis resulting in degeneration and ageing. The role of mitochondria or mitochondrial DNA (mtDNA) integrity in SSC homeostasis is unknown. Mutator mice, which harbour proof-reading deficient mitochondrial DNA polymerase gamma, accumulate mtDNA point mutations and develop a premature ageing phenotype, whereas Deletor mice, a model for adult-onset mitochondrial myopathy, accumulate mtDNA deletions and have a normal lifespan. Accumulation of mtDNA mutations and respiratory chain (RC) defect are thought to contribute to ageing process, and the Mutator mouse was the first experimental evidence supporting this theory. The aim of this thesis work was to elucidate somatic stem cell function in both Mutator and Deletor models, to investigate whether SSC dysfunction might explain the premature ageing phenotype. Our results show that the Mutator mouse accumulates mtDNA point mutations in SSC compartments, leading to changes in SSC function already during embryonal development. Deletors do not accumulate mtDNA deletions in SSCs and have normal SSC function. This suggests that premature ageing of Mutators is due to disrupted SSC homeostasis. Hematopoietic progenitors are especially sensitive to mtDNA mutagenesis, which may partly explain the high prevalence of anemia without iron deficiency seen in elderly humans. In this thesis, a novel mechanism for mitochondrial anemias is presented. MtDNA mutagenesis in hematopoietic precursors modifies signaling which causes aberrant iron loading and delayed mitochondrial clearance from maturing erythrocytes. In consequence, Mutator mice have abnormal circulating erythrocytes carrying mitochondria, which are prematurely captured and destructed by splenic macrophages, leading to iron accumulation in spleen. Enhanced destruction of newly-born erythrocytes and concurrently depleted iron stores in the bone marrow make compensatory reticulocytosis inefficient. Delayed mitochondrial clearance was also detected in a human patient with Pearson s syndrome, a rare disorder caused by a sporadic single large mtDNA deletion and causing life-threatening anemia. Treatment with N-acetyl-L-cysteine (NAC), a glutathione precursor and a ROS scavenger, was able to rescue the SSC phenotype during embryogenesis and to normalize iron loading in vitro, suggesting that mtDNA mutagenesis affects ROS signaling. However, NAC could not prevent anemia in vivo, nor rescue delayed mitochondrial clearance in vitro. This indicates that signaling in the SSC compartment is different during embryogenesis than in adulthood. This thesis shows that mtDNA integrity is essential for SSC function. Further, a new and essential role is proposed for mitochondria in regulating their own removal from maturing reticulocytes. Kudosten kantasolut ylläpitävät…