(The) role of estrogen-related receptor γ (ERRγ) in the pancreatic exocrine gland

Abstract

Mitochondrial dysfunction obstructs the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disease. However, the mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, I identify orphan nuclear receptor, estrogen-related receptor γ (ERRγ), as a key regulator of acinar cell mitochondrial homeostasis and energy production. Blocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss-of-ERRγ in primary acini abrogates mRNA expression and protein levels of mitochondrial oxidative phosphorylation (OXPHOS) complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion induces production of reactive oxygen species, ER stress and autophagy dysfunction, which in turn leads to acinar cell death. Interestingly, remaining ERRγ-deficient acinar cells that escape cell death transdifferentiate into duct-like progenitor cells indicating a role for ERRγ in acinar-to-ductal metaplasia. Indeed, ERRγ expression progressively decreases during pancreatic cancer progression and gain-of-ERRγ in pancreatic cancer cells inhibits proliferation via upregulation of CDKN1A (P21) and aberrant centrosome amplification. Taken together, our findings uncover the essential function of ERRγ in maintaining cellular metabolism, function, and, identity of the pancreatic acinar cell.