Abstract
Aging is accompanied by a general decline in the function of many cellular pathways. However, whether these are causally or functionally interconnected remains elusive. Here, we study the effect of mitochondrial–nuclear communication on stem cell aging. We show that aged mesenchymal stem cells 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). We demonstrate that aged cells showed 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 mesenchymal stem cells. Collectively, our results establish a tight, age-dependent connection between mitochondrial quality control, chromatin and stem cell fate, which are linked together by CiC.
Highlights
Aging is accompanied by a general decline in the function of many cellular pathways
Since only 500–1,000 mesenchymal stem cells (MSCs) could be isolated per mouse following this procedure, we modified the protocol by adding the possibility for outgrowth of more MSCs from bones in vitro, before cell sorting, to acquire sufficient cells for biochemical assays (~40,000 cells per mouse)
We show that MSCs from both age groups differentiate efficiently into adipocytes and osteoblasts, whereas aged MSCs show impaired osteogenic capacity (Extended Data Fig. 2c–j)
Summary
Aging is accompanied by a general decline in the function of many cellular pathways. whether these are causally or functionally interconnected remains elusive. We show that aged mesenchymal stem cells exhibit reduced chromatin accessibility and lower histone acetylation, on promoters and enhancers of osteogenic genes. Partial reprogramming in various tissues was found to promote tissue regeneration and to prolong lifespan in premature aging models[10], strongly suggesting that interfering with epigenetic mechanisms is a powerful tool to intervene in the aging process In this context, it is important to highlight that metabolism and chromatin are heavily intertwined[11,12,13,14]. Intracellular metabolism provides metabolites that serve as essential cofactors and substrates for chromatin-modifying enzymes and their availability can strongly affect the activity of these enzymes Many of these metabolites are generated in mitochondria and this establishes a tight mitochondrial–nuclear connection[15]. Acetyl-CoA levels directly affect the levels of histone acetylation, independently of the HAT enzymatic activity[16,17,18,19], due to the fact that the Michaelis constant (Km) of most HATs falls within the range of the cellular acetyl-CoA concentration[20]
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