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

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.

• Authors: 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, John W Elrod
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 4509 (10 04 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 31586055 (Publication Type: Journal Article)

Chemical References

• Calcium Channels
• Calcium-Binding Proteins
• Ketoglutaric Acids
• MICU1 protein, mouse
• Mcu protein, mouse
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Proteins

Topics

• Animals
• Calcium Channels (genetics, metabolism)
• Calcium Signaling (physiology)
• Calcium-Binding Proteins (metabolism)
• Cell Differentiation (genetics)
• DNA Methylation (physiology)
• Disease Models, Animal
• Embryo, Mammalian
• Epigenesis, Genetic (physiology)
• Epigenome
• Female
• Fibrosis
• Glycolysis (physiology)
• Humans
• Ketoglutaric Acids (metabolism)
• Mice
• Mice, Knockout
• Mitochondria (metabolism)
• Mitochondrial Membrane Transport Proteins (metabolism)
• Mitochondrial Proteins (genetics, metabolism)
• Myocardial Infarction (diagnostic imaging, etiology, pathology)
• Myocardium (cytology, pathology)
• Myofibroblasts (physiology)
• Primary Cell Culture