Nuclear receptor Nur77 and Yin‐Yang 1 synergistically increase mitochondrial abundance and activity in macrophages

Mitochondrial biogenesis requires precise regulation of both mitochondrial‐encoded and nuclear‐encoded genes. Nuclear receptor Nur77 is known to regulate mitochondrial metabolism in macrophages and skeletal muscle. Here, we compared genome‐wide Nur77 binding site and target gene expression in these two cell types, which revealed conserved regulation of mitochondrial genes and enrichment of motifs for the transcription factor Yin‐Yang 1 (YY1). We show that Nur77 and YY1 interact, that YY1 increases Nur77 activity, and that their binding sites are co‐enriched at mitochondrial ribosomal protein gene loci in macrophages. Nur77 and YY1 co‐expression synergistically increases Mrpl1 expression as well as mitochondrial abundance and activity in macrophages but not skeletal muscle. As such, we identify a macrophage‐specific Nur77‐YY1 interaction that enhances mitochondrial metabolism.