PI5P4Ks drive metabolic homeostasis through peroxisome-mitochondria interplay

• DOI: 10.1016/j.devcel.2021.04.019
• Publication Date: 2021-05-12T14:58:20Z
• Authors: Archna Ravi; Lavinia Palamiuc; Ryan M. Loughran; Joanna Triscott; Gurpreet K. Arora; Avi Kumar; Vivian Tieu; Chantal Pauli; Matthias Reist; Rachel J. Lew; Shauna L. Houlihan; Christof Fellmann; Christian Metallo; Mark A. Rubin; Brooke M. Emerling
• Keywords: Male; 0301 basic medicine; sarcoma; Carcinogenesis; lipid droplet; 610 Medicine & health; Cell Line; 1309 Developmental Biology; 1307 Cell Biology; Mice; 03 medical and health sciences; 1300 General Biochemistry, Genetics and Molecular Biology; lipid; 10049 Institute of Pathology and Molecular Pathology; Cell Line, Tumor; Neoplasms; 1312 Molecular Biology; 5-P(2); Peroxisomes; cancer; Animals; Homeostasis; Humans; PI-5-P; peroxisome; PI-4; Tumor; Lipid Droplets; Lipid Metabolism; phosphoinositide kinase; phosphoinositide; Mitochondria; mitochondria; Phosphotransferases (Alcohol Group Acceptor); β-oxidation; PI5P4Ks; Female; fatty acid; Energy Metabolism; metabolism

PI5P4Ks are a class of phosphoinositide kinases that phosphorylate PI-5-P to PI-4,5-P2. Distinct localization of phosphoinositides is fundamental for a multitude of cellular functions. Here, we identify a role for peroxisomal PI-4,5-P2 generated by the PI5P4Ks in maintaining energy balance. We demonstrate that PI-4,5-P2 regulates peroxisomal fatty acid oxidation by mediating trafficking of lipid droplets to peroxisomes, which is essential for sustaining mitochondrial metabolism. Using fluorescent-tagged lipids and metabolite tracing, we show that loss of the PI5P4Ks significantly impairs lipid uptake and β-oxidation in the mitochondria. Further, loss of PI5P4Ks results in dramatic alterations in mitochondrial structural and functional integrity, which under nutrient deprivation is further exacerbated, causing cell death. Notably, inhibition of the PI5P4Ks in cancer cells and mouse tumor models leads to decreased cell viability and tumor growth, respectively. Together, these studies reveal an unexplored role for PI5P4Ks in preserving metabolic homeostasis, which is necessary for tumorigenesis.