Proceedings of The Physiological Society

Mitochondria: Form and function (London, UK) (2017) Proc Physiol Soc 38, SA02

Research Symposium

Mitochondrial bioenergetic signaling drives myofibroblast differentiation

J. Elrod1

1. Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania, United States.

When the heart is injured quiescent fibroblasts differentiate into contractile, synthetic myofibroblasts. Initially fibrosis is reparative, but when chronic it becomes maladaptive and contributes to heart failure progression. Cytosolic Ca2+ (cCa2+) signaling is reported to be necessary for myofibroblast transdifferentiation, yet the role of mitochondrial Ca2+ (mCa2+) exchange has not been explored. cCa2+ signaling is rapidly integrated into the mitochondrial matrix via the mCa2+ uniporter channel (MCUc). To examine the contribution of mCa2+ in cardiac fibrosis, we generated conditional, fibroblast-specific Mcu knockout mice (KO) to ablate mCa2+ uptake. KO and control mice were subjected to myocardial infarction and cardiac function was examined by echocardiography. Loss of mCa2+ uptake worsened left ventricular function and increased fibrosis. To examine the cellular mechanisms responsible for the increased fibrosis we isolated mouse embryonic fibroblasts (MEFs) from Mcufl/fl mice and deleted Mcu with Cre-adenovirus. When challenged with pro-fibrotic ligands (TGF-β and AngII), Mcu-/- MEFs exhibited decreased mCa2+ uptake and enhanced cCa2+ transient amplitude. Loss of Mcu promoted myofibroblast differentiation, including increased α-SMA expression and enhanced contractile function. Mcu-/- MEFs were more glycolytic with increased phosphorylation (inactivation) of pyruvate dehydrogenase. Genetic activation of glycolysis, with a ‘glyco-high' mutant construct, was sufficient to promote myofibroblast differentiation in WT fibroblasts. Conversely, genetic inhibition of glycolytic flux ablated the enhanced differentiation observed in Mcu-/- fibroblasts. Our results suggest that alterations in mCa2+ uptake and bioenergetic pathways are necessary for myofibroblast differentiation. Thus, energetic signaling represents a novel therapeutic target to impede HF progression and other progressive fibrotic diseases.

Where applicable, experiments conform with Society ethical requirements