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Stendomycin selectively inhibits TIM23-dependent mitochondrial protein import

Ireos Filipuzzi1, Janos Steffen2, Mitchel Germain1

  • 1Novartis Institutes for BioMedical Research, Basel, Switzerland.

Nature Chemical Biology
|October 10, 2017
PubMed

Insights

Stendomycin specifically inhibits the TIM23 complex, a key mitochondrial machinery. This discovery provides a new tool for studying mitochondrial protein import and mitophagy.

Area of Science:

  • Mitochondrial biology
  • Molecular cell biology
  • Biochemistry

Background:

  • The TIM23 complex is essential for protein translocation across the mitochondrial inner membrane.
  • Specific chemical inhibitors for TIM23-dependent protein import were previously unavailable.
  • Mitochondrial protein import is crucial for cellular function and mitophagy regulation.

Purpose of the Study:

  • To identify and characterize a specific inhibitor of the TIM23 complex.
  • To investigate the role of the TIM23 complex in PINK1 stabilization and mitophagy initiation.

Main Methods:

  • Screening for natural products with inhibitory activity against the TIM23 complex.
  • Testing stendomycin's specificity and potency in yeast and mammalian cell models.
  • Analyzing the effect of stendomycin on PINK1 processing and mitochondrial localization.

Main Results:

  • Stendomycin was identified as a potent and specific inhibitor of the TIM23 complex.
  • Stendomycin treatment did not affect PINK1 processing.
  • TIM23 is essential for stabilizing PINK1 on the mitochondrial outer membrane to trigger mitophagy.

Conclusions:

  • Stendomycin is a valuable chemical probe for studying TIM23 function.
  • The TIM23 complex plays a critical role in PINK1-mediated mitophagy initiation.
  • Targeting the TIM23 complex offers new avenues for understanding mitochondrial dynamics and disease.

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