The ageing epigenome regulates stem cell fate via mitochondrial-derived vesicles delivery of citrate carrier to lysosomes [CUT&RUN]

We report that upon ageing MSC exhibit reduced metabolic rates, with lower lipid biosynthesis and elevated acetyl-CoA levels. However, aged cells display chromatin compaction and histone hypo-acetylation, particularly on enhancers of genes involved in osteogenesis. This is due to the lower levels of citrate carrier, resulting in impaired acetyl-CoA export from mitochondria to the cytosol, which concomitantly affects histone acetylation and osteogenesis. CiC gets degraded in the aged cells via an MVD-lysosomal pathway, which establishes a strong connection between mitochondrial quality control, chromatin and stemness. Description of aged-associated changes in metabolism, chromatin and stemness using mesenchymal stem cells isolated from young and old mice.