Chaperoning mitochondrial permeability transition: regulation of transition pore complex by a J-protein, DnaJC15

Cell Death Dis. 2014 Mar 6;5(3):e1101. doi: 10.1038/cddis.2014.72.

Abstract

Mitochondria have a central role in the intrinsic pathway of apoptosis and involve activation of several transmembrane channels leading to release of death factors. Reduced expression of a mitochondrial J-protein DnaJC15 was associated with the development of chemoresistance in ovarian cancer cells. DnaJC15 was found to be a part of mitochondrial protein-transport machinery, though its connection with cell death mechanisms is still unclear. In the present study, we have provided evidence towards a novel function of DnaJC15 in regulation of mitochondrial permeability transition pore (MPTP) complex in normal and cancer cells. Overexpression of DnaJC15 resulted in MPTP opening and induction of apoptosis, whereas reduced amount of protein suppressed MPTP activation, upon cisplatin treatment. DnaJC15 was found to exert its proapoptotic function through the essential component of MPTP, cyclophilin D (CypD). Our results reveal a specific role of DnaJC15 in recruitment and coupling of CypD with mitochondrial permeability transition. In summary, our analysis provides first-time insights on the functional connection between mitochondrial inner membrane protein translocation machinery-associated J-protein DnaJC15 and regulation of cell death pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cisplatin / pharmacology
  • Cyclophilins / genetics
  • Cyclophilins / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Genotype
  • HEK293 Cells
  • HSP40 Heat-Shock Proteins / genetics
  • HSP40 Heat-Shock Proteins / metabolism*
  • Humans
  • MCF-7 Cells
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mitochondrial Membrane Transport Proteins / drug effects
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Membranes / drug effects
  • Mitochondrial Membranes / metabolism*
  • Mitochondrial Membranes / pathology
  • Mutation
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Phenotype
  • RNA Interference
  • Time Factors
  • Transfection

Substances

  • Antineoplastic Agents
  • DNAJC15 protein, human
  • HSP40 Heat-Shock Proteins
  • Mitochondrial Membrane Transport Proteins
  • mitochondrial permeability transition pore
  • Cyclophilins
  • PPID protein, human
  • Cisplatin