PI5P4Ks drive metabolic homeostasis through peroxisome-mitochondria interplay

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. [Display omitted] •PI-4,5-P2 generated at peroxisomes by PI5P4Ks is essential for lipid trafficking•Loss of PI5P4K activity leads to peroxisomal dysfunction and accumulation of VLCFAs•PI5P4K inhibition impairs mitochondrial function downstream of peroxisomes•Therapeutic rationale for targeting PI5P4Ks for metabolically vulnerable diseases Ravi et al. demonstrate that PI5P4K activity is required for maintaining energy homeostasis by regulating the crosstalk between peroxisomes and mitochondria. Their findings suggest that the metabolic susceptibility induced by PI5P4K inhibition can be exploited for treating diseases such as cancer.