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.
Highlights
(JC19) and DnaJC15 (JC15) governing the primary protein import activity.[4,5] JC19 is ubiquitously expressed in all tissues, but the expression profile of JC15 is regulated by the methylation status of the CpG islands at the promoter region.[6]
A prototypical mitochondrial permeability transition (MTP) pore (MPTP) is composed of voltage-dependent anion channel (VDAC), adenine nucleotide translocator (ANT) and a peptidyl-proline isomerase cyclophilin D (CypD)
It has been proposed that MPTP complex is constituted by a dimer of Fo–F1 adenosine triphosphate (ATP) synthase, which is incorporated in the lipid bilayers to form Ca2 þ -activated channels.[16]
Summary
(JC19) and DnaJC15 (JC15) governing the primary protein import activity.[4,5] JC19 is ubiquitously expressed in all tissues, but the expression profile of JC15 is regulated by the methylation status of the CpG islands at the promoter region.[6]. It has been proposed that MPTP complex is constituted by a dimer of Fo–F1 adenosine triphosphate (ATP) synthase, which is incorporated in the lipid bilayers to form Ca2 þ -activated channels.[16] The regulator of MPTP, CypD associates with the lateral stalk of ATP synthase and binds with the OSCP (oligomycin sensitivity-conferring protein) subunit in a Pi (inorganic phosphate)-dependent manner.[16] In response to pro-apoptotic stimuli, MPTP assumes a higher conductance state that allows disregulated entry of small molecules causing loss of potential, osmotic imbalance and organellar disintegration.[12] Recent reports have shown VDAC and ANT to be dispensable for MPTP activation and mouse knocked out for either of the proteins still undergo permeability transition.[17] Mouse lacking CypD show enhanced resistance to cell death and activation of the MPTP, highlighting its essential role at the channel.[18] the exact molecular details of the process are still not identified
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