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- Title
Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation.
- Authors
Lombardi, Alyssa A.; Gibb, Andrew A.; Arif, Ehtesham; Kolmetzky, Devin W.; Tomar, Dhanendra; Luongo, Timothy S.; Jadiya, Pooja; Murray, Emma K.; Lorkiewicz, Pawel K.; Hajnóczky, György; Murphy, Elizabeth; Arany, Zoltan P.; Kelly, Daniel P.; Margulies, Kenneth B.; Hill, Bradford G.; Elrod, John W.
- Abstract
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 (mCa2+) 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 mCa2+ uptake and induce coordinated changes in metabolism, i.e., increased glycolysis feeding anabolic pathways and glutaminolysis yielding increased α-ketoglutarate (αKG) bioavailability. mCa2+-dependent metabolic reprogramming leads to the activation of αKG-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 mCa2+ signaling regulates the epigenome to influence cellular differentiation. Myofibroblast differentiation contributes to extracellular matrix remodeling and fibrosis. Here, the authors report that alterations in mitochondrial calcium uptake is essential for metabolic reprogramming and epigenetic signaling for activation of the myofibroblast gene program.
- Subjects
METABOLISM; CELL differentiation; FIBROBLASTS; MYOFIBROBLASTS; CELL death
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-12103-x