FKBP4 regulates 5-fluorouracil sensitivity in colon cancer by controlling mitochondrial respiration

Life Sci Alliance. 2022 Aug 18;5(11):e202201413. doi: 10.26508/lsa.202201413. Print 2022 Nov.

Abstract

Mitochondrial respiration and metabolism play a key role in the pathogenesis and progression of colon adenocarcinoma (COAD). Here, we report a functional pool of FKBP4, a co-chaperone protein, in the mitochondrial intermembrane space (IMS) of colon cancer cells. We found that IMS-localized FKBP4 is essential for the maintenance of mitochondrial respiration, thus contributing to the sensitivity of COAD cells to 5-fluorouracil (5-FU). Mechanistically, FKBP4 interacts with COA6 and controls the assembly of the mitochondrial COA6/SCO1/SCO2 complex, thereby governing COA6-regulated biogenesis and activity of mitochondrial cytochrome c oxidase (complex IV). Thus, our data reveal IMS-localized FKBP4 as a novel regulator of 5-FU sensitivity in COAD, linking mitochondrial respiration to 5-FU sensitivity in COAD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma* / drug therapy
  • Adenocarcinoma* / genetics
  • Carrier Proteins / metabolism
  • Colonic Neoplasms* / drug therapy
  • Colonic Neoplasms* / genetics
  • Copper / metabolism
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism
  • Fluorouracil / pharmacology
  • Humans
  • Mitochondrial Proteins / metabolism
  • Molecular Chaperones / metabolism
  • Respiration
  • Tacrolimus Binding Proteins

Substances

  • COA6 protein, human
  • Carrier Proteins
  • Mitochondrial Proteins
  • Molecular Chaperones
  • SCO1 protein, human
  • Copper
  • Electron Transport Complex IV
  • Tacrolimus Binding Proteins
  • tacrolimus binding protein 4
  • Fluorouracil