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A mitochondrial ubiquitin ligase MITOL controls cell toxicity of polyglutamine-expanded protein

Ayumu Sugiura1, Ryo Yonashiro, Toshifumi Fukuda

  • 1Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.

Mitochondrion
|September 21, 2010
PubMed

Insights

MITOL, a mitochondrial ligase, degrades toxic ataxin-3 protein in mitochondria. This protects against polyglutamine (polyQ) diseases by preventing mitochondrial dysfunction and cell death.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Polyglutamine (polyQ) tract expansion in ataxin-3 causes Machado-Joseph disease, a neurodegenerative disorder.
  • Pathogenic polyQ proteins accumulate in mitochondria, leading to mitochondrial dysfunction.

Purpose of the Study:

  • Investigate the role of MITOL, a mitochondrial outer membrane ubiquitin ligase, in degrading pathogenic ataxin-3.
  • Elucidate the mechanism of mitochondrial quality control involving MITOL and the ubiquitin-proteasome pathway.

Main Methods:

  • Utilized N-terminal-truncated pathogenic ataxin-3 with a 71-glutamine repeat (ΔNAT-3Q71).
  • Assessed the effect of MITOL on ΔNAT-3Q71 degradation and mitochondrial accumulation.
  • Examined consequences of MITOL knockdown, including aggregate formation and cell death markers.

Main Results:

  • MITOL promoted the degradation of ΔNAT-3Q71 via the ubiquitin-proteasome pathway.
  • MITOL attenuated the accumulation of ΔNAT-3Q71 within mitochondria.
  • MITOL knockdown led to insoluble ΔNAT-3Q71 aggregates, cytochrome c release, and cell death.

Conclusions:

  • MITOL plays a protective role against polyglutamine toxicity by clearing pathogenic ataxin-3 from mitochondria.
  • MITOL-mediated ubiquitin-proteasome pathway at the mitochondrial outer membrane is a key protein quality-control mechanism.
  • MITOL represents a potential therapeutic target for polyglutamine diseases.

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