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Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activity

Claudio Laquatra1, Alessia Magro2, Federica Guarra3

  • 1Department of Biomedical Sciences, University of Padova, Padova, Italy. claudio.laquatra@unipd.it.

Cell Death & Disease
|March 13, 2025
PubMed

Insights

Mitochondrial chaperone TRAP1 mutations impact its structure, stability, and function, affecting cellular homeostasis and disease progression. This study reveals how specific mutations alter TRAP1 activity and its role in cancer.

Area of Science:

  • Mitochondrial biology
  • Structural biology
  • Molecular dynamics

Background:

  • The mitochondrial chaperone TRAP1 regulates cellular homeostasis, with implications in neurodegeneration, ischemia, and cancer.
  • TRAP1 mutations are linked to disorders, but the structural basis for their functional impact remains unstudied.

Purpose of the Study:

  • To investigate the structural and functional consequences of five specific TRAP1 mutations.
  • To elucidate the structure-activity relationship of TRAP1 and identify key regulatory residues.

Main Methods:

  • Utilized a modular structure-based framework.
  • Performed molecular dynamics simulations to analyze mutation effects.
  • Assessed impacts on TRAP1 stability, dynamics, and ATPase activity.
  • Evaluated effects on TRAP1 interactor succinate dehydrogenase (SDH) activity.

Main Results:

  • Each mutation differentially affected TRAP1's long-range interactions, dynamics, and ATPase activity.
  • Mutations altered SDH activity, indicating functional changes in TRAP1.
  • TRAP1 mutations impacted aggressive sarcoma cell growth, migration, and drug sensitivity.

Conclusions:

  • Provides novel insights into the structure-activity relationship of TRAP1.
  • Identifies critical amino acid residues governing TRAP1 proteostatic and pro-neoplastic functions.
  • Highlights the potential of targeting TRAP1 in cancer therapy.

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