Pleckstrin homology domain of p210 BCR-ABL interacts with cardiolipin to regulate its mitochondrial translocation and subsequent mitophagy

Kentaro Shimasaki, Miho Watanabe-Takahashi, Masato Umeda, Satoru Funamoto, Yoshiro Saito, Noriko Noguchi, Keigo Kumagai, Kentaro Hanada, Fujiko Tsukahara, Yoshiro Maru, Norihito Shibata, Mikihiko Naito, Kiyotaka Nishikawa

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Chronic myeloid leukemia (CML) is caused by the chimeric protein p210 BCR-ABL encoded by a gene on the Philadelphia chromosome. Although the kinase domain of p210 BCR-ABL is an active driver of CML, the pathological role of its pleckstrin homology (PH) domain remains unclear. Here, we carried out phospholipid vesicle-binding assays to show that cardiolipin (CL), a characteristic mitochondrial phospholipid, is a unique ligand of the PH domain. Arg726, a basic amino acid in the ligand-binding region, was crucial for ligand recognition. A subset of wild-type p210 BCR-ABL that was transiently expressed in HEK293 cells was dramatically translocated from the cytosol to mitochondria in response to carbonyl cyanide m-chlorophenylhydrazone (CCCP) treatment, which induces mitochondrial depolarization and subsequent externalization of CL to the organelle's outer membrane, whereas an R726A mutant of the protein was not translocated. Furthermore, only wild-type p210 BCR-ABL, but not the R726A mutant, suppressed CCCP-induced mitophagy and subsequently enhanced reactive oxygen species production. Thus, p210 BCR-ABL can change its intracellular localization via interactions between the PH domain and CL to cope with mitochondrial damage. This suggests that p210 BCR-ABL could have beneficial effects for cancer proliferation, providing new insight into the PH domain's contribution to CML pathogenesis.

Original languageEnglish
Pages (from-to)22-34
Number of pages13
JournalGenes to Cells
Volume23
Issue number1
DOIs
Publication statusPublished - 2018 Jan
Externally publishedYes

Keywords

  • cardiolipin
  • mitochondria
  • mitophagy
  • p210 BCR-ABL
  • pleckstrin homology domain
  • reactive oxygen species

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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