Dataset Information

Proteomic analysis of U2OS cells treated with the dihydroorotate dehydrogenase (DHODH) inhibitor Brequinar

ABSTRACT: The mitochondrial respiratory chain assembles into higher order complexes termed supercomplexes (SCs) under certain physiological or metabolic stimuli. A small molecule screen developed by the lab identified DHODH inhibitors as potent activators of SC assembly in cancer cells. To investigate the proteomic regulation of SCs under nucleotide deficiency, we treated U2OS cells for 48 hours with Brequinar (500 nM). Proteomic analysis highlighted strong signatures of respiratory chain subunit abundance and peroxisomal-derived ether phospholipid synthesis enzymes. Bypassing DHODH inhibition through uridine supplementation prevented these alterations. These findings establish a coordinated cellular response to reduced nucleotide pools that stimulates ether phospholipid synthesis and respiratory chain supra-assembly.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte, Cell Culture

DISEASE(S): Disease Free

SUBMITTER: mark Jedrychowski

LAB HEAD: Pere Puigserver

PROVIDER: PXD023882 | Pride | 2022-02-16

REPOSITORIES: Pride

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Publications

Peroxisomal-derived ether phospholipids link nucleotides to respirasome assembly.

Bennett Christopher F CF O'Malley Katherine E KE Perry Elizabeth A EA Balsa Eduardo E Latorre-Muro Pedro P Riley Christopher L CL Luo Chi C Jedrychowski Mark M Gygi Steven P SP Puigserver Pere P

Nature chemical biology 20210315 6

The protein complexes of the mitochondrial electron transport chain exist in isolation and in higher order assemblies termed supercomplexes (SCs) or respirasomes (SC I+III<sub>2</sub>+IV). The association of complexes I, III and IV into the respirasome is regulated by unknown mechanisms. Here, we designed a nanoluciferase complementation reporter for complex III and IV proximity to determine in vivo respirasome levels. In a chemical screen, we found that inhibitors of the de novo pyrimidine synt ...[more]

PMID: 33723432

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