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Nek4 regulates mitochondrial respiration and morphology

Fernanda Luisa Basei1,2, Camila de Castro Ferezin1,3, Ana Luisa Rodrigues de Oliveira1,3

  • 1Faculdade de Ciências Farmacêuticas, Universidade Estadual de Campinas, Brazil.

The FEBS Journal
|January 5, 2022
PubMed

Insights

Nek4 kinase enhances cancer cell survival by boosting mitochondrial respiration and ATP production. This study reveals Nek4 as a key regulator of mitochondrial function and fragmentation.

Area of Science:

  • Mitochondrial biology
  • Cancer cell biology
  • Molecular oncology

Background:

  • Nek4 (Never in mitosis gene A-related kinase 4) is a serine/threonine kinase involved in primary cilia stabilization, DNA damage response, autophagy, and epithelial-to-mesenchymal transition.
  • Nek4's role in cancer cell survival and chemotherapy resistance is established, but its precise mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the precise mechanisms of Nek4 function in cancer cells.
  • To investigate the role of Nek4 in regulating mitochondrial respiration, ATP production, and mitochondrial dynamics.

Main Methods:

  • Overexpression and depletion of Nek4 in cancer cell lines.
  • Measurement of mitochondrial respiration and ATP production.
  • Assessment of mitochondrial membrane potential and mitochondrial DNA (mtDNA) integrity.
  • Analysis of mitochondrial morphology (elongation/fission) and DRP1 (dynamin-related protein 1) phosphorylation.
  • Inhibition of DRP1 to assess its role in Nek4-mediated effects.

Main Results:

  • Nek4 overexpression activated mitochondrial respiration and ATP production, increasing mitochondrial membrane potential and resistance to mtDNA damage.
  • Nek4 depletion reduced mitochondrial respiration and mtDNA integrity.
  • Nek4 deficiency led to mitochondrial elongation, likely due to reduced DRP1 activity.
  • Nek4 overexpression promoted mitochondrial fission, associated with enhanced DRP1 and Erk1/2 phosphorylation.
  • Inhibition of DRP1 abolished the effects of Nek4 on mitochondrial respiration.

Conclusions:

  • Nek4 is a novel regulator of mitochondrial function, impacting respiration, ATP production, and dynamics.
  • Nek4-mediated mitochondrial fragmentation and enhanced respiration may contribute to cancer cell survival and chemotherapy resistance.
  • The findings suggest a link between Nek4, DRP1 phosphorylation, and mitochondrial fragmentation, offering potential therapeutic targets in oncology.
Keywords:
DRP1Nek4fissionmitochondrial function

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