| Popis: |
Ageing is accompanied by a general decline in the function of many cellular pathways. Although the contribution of each individual pathway in ageing has been extensively studied over the last years, how these pathways crosstalk to regulate the development and progression of ageing remained elusive. Here, I sought to determine whether ageassociated changes in mitochondrial function, epigenetic modifications and stem cell activity are causally or functionally interconnected. Therefore, I studied the effects of mitochondrial–nuclear communication on stem cell function upon ageing. I found that aged mesenchymal stem cells isolated from the bone marrow (BM-MSCs) exhibit reduced chromatin accessibility and lower histone acetylation, particularly on promoters and enhancers of osteogenic genes. The reduced histone acetylation is due to impaired export of mitochondrial acetyl-CoA, owing to the lower levels of citrate carrier (CiC). I demonstrated that aged cells show enhanced lysosomal degradation of CiC, which is mediated via mitochondrial-derived vesicles. Strikingly, restoring cytosolic acetyl-CoA levels either by exogenous CiC expression or via acetate supplementation, remodels the chromatin landscape and rescues the osteogenesis defects of aged BM-MSCs. Collectively, my results establish a tight, age-dependent connection between mitochondrial quality control, chromatin and stem cell fate, which are altogether linked by CiC. The bone marrow stroma is characterized by low oxygen concentration (hypoxia), which is essential for the maintenance of BM-MSC stemness. However, in vitro BMMSC culture during stem cell therapies is performed under high oxygen conditions (normoxia), which could dramatically impact BM-MSC activity. Here, I explored how the metabolism-chromatin-stemness axis is affected by oxygen tension. I found that high oxygen impairs osteogenesis irreversibly, due to higher chromatin compaction and lower histone acetylation on promoters and enhancers of osteogenic genes. Although normoxia induces a metabolic switch which results in production of higher acetyl-CoA levels, I showed that this remains trapped inside the mitochondria, potentially due to lower CiC activity. Impressively, modulating CiC function impacts both the metabolic and the epigenetic profile of BM-MSCs, whereas exogenous supplementation with acetate restores the osteogenic differentiation capacity of normoxia-cultured cells. |
