Abstract 17355: Mitochondrial Calcium Uptake Regulates Lung Alveolar Epithelial Regeneration by Connecting Mitochondrial Metabolism With Epigenetic Changes

Abstract

Introduction: Lung disease is the third leading cause of death and expanding. The endogenous regeneration of lung alveolar epithelium is severely compromised with age and chronic lung disease resulting in deaths after infections such as COVID-19. Mammalian lung alveolar epithelium consists of: alveolar epithelial type 1 and type 2 cells (AT1 and AT2). Stem/progenitor AT2 cells trans-differentiate into the gas exchanging AT1 cells in response to injury and regenerate the lost alveolar epithelium. Molecular mechanism of AT2-to-AT1 cell differentiation is unknown and its identification is critical for therapeutic development. Mitochondrial calcium controls fundamental cellular processes such as ATP production, metabolism, cell death etc. Dysregulation of mitochondrial calcium is implicated in diabetes, heart failure and neurodegeneration. Mitochondrial calcium uptake 1 (MICU1) negatively regulates mitochondrial calcium uptake which affects downstream signaling such as metabolite bioavailability and epigenetics. Results: We have identified a remarkable increase in MICU1 expression and a decrease in mitochondrial calcium uptake in AT2 cells during AT2-to-AT1 cell differentiation in adult mice after bacterial lung infection injury. Micu1 knockout in AT2 cells resulted in mitochondrial calcium overload, reduced AT2-to-AT1 cell differentiation and impaired lung regeneration after lung injury in mice. MICU1-dependent mitochondrial calcium regulated the citric acid cycle metabolite, α-ketoglutarate in AT2 cells. The metabolite, α-ketoglutarate, also functions as a signaling molecule and alters cellular epigenetics by activating Jumonji C domain containing histone lysine demethylases. Micu1 knockout AT2 cells exhibited α-ketoglutarate downregulation and the epigenetic change of H3K9 hypermethylation. Pharmacological inhibition of Jumonji histone demethylase in mouse AT2 cells increased H3K9me3 level and completely blocked AT2-to-AT1 cell differentiation in vitro. Conclusions: Overall, the results suggest that MICU1-mediated mitochondrial calcium uptake plays a key role in AT2-to-AT1 cell differentiation and lung alveolar epithelial regeneration by linking mitochondrial metabolism with epigenetics.