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Outer mitochondrial membrane E3 Ub ligase MARCH5 controls de novo peroxisome biogenesis

Nicolas Verhoeven1, Yumiko Oshima1, Etienne Cartier1

  • 1Center for Biomedical Engineering and Technology, University Hospital Basel, University of Basel, Basel, Switzerland; Department of Biochemistry and Molecular Biology, University Hospital Basel, University of Basel, Basel, Switzerland.

Developmental Cell
|October 18, 2024
PubMed

Insights

The E3 ubiquitin ligase MARCH5 is crucial for creating peroxisomes from mitochondria. Its absence impairs peroxisome formation and function, highlighting MARCH5

Area of Science:

  • Cell Biology
  • Mitochondrial Biology
  • Peroxisome Biogenesis

Background:

  • Peroxisomes are essential organelles involved in various metabolic processes.
  • The biogenesis of peroxisomes is a complex process involving multiple protein factors.
  • Mitochondria have been implicated in peroxisome formation, but the underlying mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the role of the outer mitochondrial membrane (OMM)-associated E3 ubiquitin ligase MARCH5 in peroxisome biogenesis.
  • To elucidate the molecular mechanisms by which MARCH5 influences the generation of mitochondria-derived pre-peroxisomes.

Main Methods:

  • Utilized CRISPR-Cas9 gene editing to create MARCH5 knockout and double knockout cell lines (MARCH5/Pex14, MARCH5/Pex3).
  • Employed immunofluorescence microscopy to visualize peroxisomes and mitochondria, and to track protein localization.
  • Analyzed protein expression levels and ubiquitination status using Western blotting and immunoprecipitation assays.

Main Results:

  • MARCH5 knockout cells exhibited accumulation of immature peroxisomes and impaired fatty-acid-induced peroxisomal biogenesis.
  • MARCH5 redistributed to peroxisomes during fatty-acid stimulation, and its ubiquitination-deficient mutants accumulated on pre-peroxisomes.
  • Depletion of Pex14, a peroxisome biogenesis factor, led to accumulation of MARCH5- and Tom20-positive pre-peroxisomes, with no peroxisomes detected in MARCH5/Pex14 double knockouts.
  • Mitochondrial function remained intact in MARCH5-deficient cells, and reduced expression of peroxisomal proteins was observed.

Conclusions:

  • MARCH5 is a key regulator essential for the generation of mitochondria-derived pre-peroxisomes.
  • MARCH5 plays a central role in mitochondria-dependent peroxisome biogenesis, independent of its function as a mitochondrial quality control factor.
  • The findings reveal a novel link between mitochondrial dynamics and peroxisome formation mediated by MARCH5.
Keywords:
MARCH5Pex14Pex3Ub E3 ligasebiogenesismetabolic adaptationmitochondriamitochondria-derived pre-peroxisomesperoxisomes

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