Function of the SRC-3 pathway in HSCs. SRC-3 is shown bound to the promoter region of the gene coding the acetyltransferase GCN5 in WT HSCs. CGN5 contributes to acetylate PGC-1α, thus inhibiting its cotranscriptional activity. This results in repression of the mitochondrial oxidative metabolism and maintenance of the quiescent state in HSCs. In SRC-3^−/− HSCs, the deacetylation state of PGC-1α is shown to prevail because of the noncounteracted activity of sirtuins (SIRTs). In this state, PGC-1α can exert its transcriptional activity upregulating the expression of genes involved in mitochondrial biogenesis. This results in increased mass of mitochondria and mtDNA copy number, higher ΔΨ_m, and enhanced OCR, ROS generation, and ATP production. The phenotype of SRC-3^−/− HSCs is characterized by loss of quiescence and lower long-term (LT) reconstitution capacity. These latter features in SRC-3^−/− HSCs are prevented by treatment with the antioxidant N-acetyl cysteine (NAC) suggesting the involvement of ROS-mediated signaling. NRFs, nuclear respiratory factors; TFAM, mitochondrial transcription factor A.