PI5P4Ks drive metabolic homeostasis through peroxisome-mitochondria interplay.

Ravi, Archna; Palamiuc, Lavinia; Loughran, Ryan M; Triscott, Joanna; Arora, Gurpreet K; Kumar, Avi; Tieu, Vivian; Pauli, Chantal; Reist, Matthias; Lew, Rachel J; Houlihan, Shauna L; Fellmann, Christof; Metallo, Christian; Rubin, Mark A.; Emerling, Brooke M (2021). PI5P4Ks drive metabolic homeostasis through peroxisome-mitochondria interplay. Developmental cell, 56(11), 1661-1676.e10. Elsevier 10.1016/j.devcel.2021.04.019

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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.

Item Type:

 Journal Article (Original Article)

Division/Institute:

 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
09 Interdisciplinary Units > Microscopy Imaging Center (MIC)

UniBE Contributor:

 Triscott, Joanna Catherine Caprio, Reist, Matthias, Rubin, Mark Andrew

Subjects:

 600 Technology > 610 Medicine & health

ISSN:

 1878-1551

Publisher:

 Elsevier

Language:

 English

Submitter:

 Marla Rittiner

Date Deposited:

 24 Jan 2022 13:20

Last Modified:

 05 Dec 2022 16:00

Publisher DOI:

 10.1016/j.devcel.2021.04.019

PubMed ID:

 33984270

Uncontrolled Keywords:

 PI-4,5-P(2) PI-5-P PI5P4Ks cancer fatty acid lipid lipid droplet metabolism mitochondria peroxisome phosphoinositide phosphoinositide kinase sarcoma β-oxidation

BORIS DOI:

 10.48350/163460

URI:

 https://boris.unibe.ch/id/eprint/163460

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