The role of mitochondrial energy metabolism in the pathogenesis of polycystic liver disease: new therapeutic strategy

Polycystic liver diseases (PLDs) are inherited genetic disorders marked by progressive development of intrahepatic, fluid-filled biliary cysts, which are a main cause of morbidity. Chronic administration of somatostatin analogs, aimed to reducing elevated intracellular cAMP levels in cystic cholangiocytes, is the current pharmacological treatment for advanced disease, but offers limited benefit. PLD-causing genes induce abnormal proteostasis and endoplasmic reticulum (ER) stress in cholangiocytes, promoting cystogenesis. Given the connection between the ER and mitochondria through the mitochondria-associated ER membranes (MAMs), the objective of this doctoral thesis is to investigate mitochondrial dynamics, bioenergetics, and metabolism in cystic cholangiocytes, their interplay with the ER, and the therapeutic regulatory value in vitro, in vivo and in patients with PLD.