Valentina C. Sladky1, Hanan Akbari1, Daniel Tapias-Gomez1, Lauren T. Evans1, Chelsea G. Drown1, Margaret A. Strong1, Gina M. LoMastro1, Tatianna Larman2 and Andrew J. Holland1 1Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; 2Divison of Gastrointestinal and Liver Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA Corresponding authors: ahollandjhmi.edu, vsladky1jhmi.edu Abstract

Hepatocyte polyploidization is a tightly controlled process that is initiated at weaning and increases with age. The proliferation of polyploid hepatocytes in vivo is restricted by the PIDDosome–P53 axis, but how this pathway is triggered remains unclear. Given that increased hepatocyte ploidy protects against malignant transformation, the evolutionary driver that sets the upper limit for hepatocyte ploidy remains unknown. Here we show that hepatocytes accumulate centrioles during cycles of polyploidization in vivo. The presence of excess mature centrioles containing ANKRD26 was required to activate the PIDDosome in polyploid cells. As a result, mice lacking centrioles in the liver or ANKRD26 exhibited increased hepatocyte ploidy. Under normal homeostatic conditions, this increase in liver ploidy did not impact organ function. However, in response to chronic liver injury, blocking centriole-mediated ploidy control leads to a massive increase in hepatocyte polyploidization, severe liver damage, and impaired liver function. These results show that hyperpolyploidization sensitizes the liver to injury, posing a trade-off for the cancer-protective effect of increased hepatocyte ploidy. Our results may have important implications for unscheduled polyploidization that frequently occurs in human patients with chronic liver disease.

Received May 9, 2022. Accepted July 27, 2022.