| First Author | Posavec Marjanović M | Year | 2017 |
| Journal | Nat Struct Mol Biol | Volume | 24 |
| Issue | 11 | Pages | 902-910 |
| PubMed ID | 28991266 | Mgi Jnum | J:325974 |
| Mgi Id | MGI:6863428 | Doi | 10.1038/nsmb.3481 |
| Citation | Posavec Marjanovic M, et al. (2017) MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD(+) consumption. Nat Struct Mol Biol 24(11):902-910 |
| abstractText | Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A1.1 contains a macrodomain capable of binding NAD(+)-derived metabolites. Here we report that macroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and that myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity. We found that the metabolite-binding macrodomain was essential for sustained optimal mitochondrial function but dispensable for gene regulation. Through direct binding, macroH2A1.1 inhibits basal poly-ADP ribose polymerase 1 (PARP-1) activity and thus reduces nuclear NAD(+) consumption. The resultant accumulation of the NAD(+) precursor NMN allows for maintenance of mitochondrial NAD(+) pools that are critical for respiration. Our data indicate that macroH2A1.1-containing chromatin regulates mitochondrial respiration by limiting nuclear NAD(+) consumption and establishing a buffer of NAD(+) precursors in differentiated cells. |
