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

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. The chimeric protein p210 BCR‐ABL causes chronic myeloid leukemia. We found that cardiolipin is a unique ligand of the PH domain of p210 BCR‐ABL. p210 BCR‐ABL was dramatically translocated from the cytosol to mitochondria in response to carbonyl cyanide m‐chlorophenylhydrazone (CCCP) treatment via interactions between the PH domain and CL to cope with mitochondrial damage.