Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation

Alyssa A. Lombardi, Andrew A. Gibb, Ehtesham Arif, Devin W. Kolmetzky, Dhanendra Tomar, Timothy S. Luongo, Pooja Jadiya, Emma K. Murray, Pawel K. Lorkiewicz, György Hajnóczky, Elizabeth Murphy, Zoltan P. Arany, Daniel P. Kelly, Kenneth B. Margulies, Bradford G. Hill and John W. Elrod ()
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Alyssa A. Lombardi: Lewis Katz School of Medicine at Temple University
Andrew A. Gibb: Lewis Katz School of Medicine at Temple University
Ehtesham Arif: Lewis Katz School of Medicine at Temple University
Devin W. Kolmetzky: Lewis Katz School of Medicine at Temple University
Dhanendra Tomar: Lewis Katz School of Medicine at Temple University
Timothy S. Luongo: Lewis Katz School of Medicine at Temple University
Pooja Jadiya: Lewis Katz School of Medicine at Temple University
Emma K. Murray: Lewis Katz School of Medicine at Temple University
Pawel K. Lorkiewicz: University of Louisville
György Hajnóczky: Thomas Jefferson University
Elizabeth Murphy: National Heart Lung and Blood Institute
Zoltan P. Arany: University of Pennsylvania
Daniel P. Kelly: University of Pennsylvania
Kenneth B. Margulies: University of Pennsylvania
Bradford G. Hill: University of Louisville
John W. Elrod: Lewis Katz School of Medicine at Temple University

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12103-x

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