| First Author | Lombardi AA | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 4509 |
| PubMed ID | 31586055 | Mgi Jnum | J:281742 |
| Mgi Id | MGI:6377725 | Doi | 10.1038/s41467-019-12103-x |
| Citation | Lombardi AA, et al. (2019) Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation. Nat Commun 10(1):4509 |
| abstractText | Fibroblast to myofibroblast differentiation is crucial for the initial healing response but excessive myofibroblast activation leads to pathological fibrosis. Therefore, it is imperative to understand the mechanisms underlying myofibroblast formation. Here we report that mitochondrial calcium (mCa(2+)) signaling is a regulatory mechanism in myofibroblast differentiation and fibrosis. We demonstrate that fibrotic signaling alters gating of the mitochondrial calcium uniporter (mtCU) in a MICU1-dependent fashion to reduce mCa(2+) uptake and induce coordinated changes in metabolism, i.e., increased glycolysis feeding anabolic pathways and glutaminolysis yielding increased alpha-ketoglutarate (alphaKG) bioavailability. mCa(2+)-dependent metabolic reprogramming leads to the activation of alphaKG-dependent histone demethylases, enhancing chromatin accessibility in loci specific to the myofibroblast gene program, resulting in differentiation. Our results uncover an important role for the mtCU beyond metabolic regulation and cell death and demonstrate that mCa(2+) signaling regulates the epigenome to influence cellular differentiation. |
