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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 Murp, 2019. "Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12103-x
    DOI: 10.1038/s41467-019-12103-x
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    Cited by:

    1. Mohammad Naimul Islam & Galina A. Gusarova & Shonit R. Das & Li Li & Eiji Monma & Murari Anjaneyulu & Liberty Mthunzi & Sadiqa K. Quadri & Edward Owusu-Ansah & Sunita Bhattacharya & Jahar Bhattacharya, 2022. "The mitochondrial calcium uniporter of pulmonary type 2 cells determines severity of acute lung injury," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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