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

Authors

Alyssa A. Lombardi, Temple University
Andrew A. Gibb, Temple University
Ehtesham Arif, Temple University
Devin W. Kolmetzky, Temple University
Dhanendra Tomar, Temple University
Timothy S. Luongo, Temple University
Pooja Jadiya, Temple University
Emma K. Murray, Temple University
Pawel K. Lorkiewicz, University of Louisville
György Hajnóczky, Thomas Jefferson UniversityFollow
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, Temple University

Document Type

Article

Publication Date

10-4-2019

Comments

This article is the author’s final published version in Nature Communications, Volume 10, Issue 1, October 2019, Article number e1151.

The published version is available at https://doi.org/Article number 4509. Copyright © Lombardi et al.

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.

Recommended Citation

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.; and Elrod, John W., "Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation." (2019). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 286.
https://jdc.jefferson.edu/pacbfp/286

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

31586055

Language

English