Trans-localization of p210 BCR-ABL to the mitochondria is mediated by the interaction of its PH domain with cardiolipin exposed on the outer membrane.

p210 BCR-ABL, a chimeric protein composed of breakpoint cluster region (BCR) and Abelson proto-oncogene (ABL) tyrosine kinase, is a principal driver of chronic myeloid leukemia (CML). We previously reported that the recombinant pleckstrin homology (PH) domain of p210 BCR-ABL (p210-PH) binds efficiently to cardiolipin (CL), a mitochondrial inner membrane-specific phospholipid, in vitro. Additionally, p210 BCR-ABL expressed in HEK293T cells trans-localizes from the cytosol to the mitochondria upon mitochondrial damage, inhibiting subsequent mitophagy and increasing reactive oxygen species production, thereby promoting CML cell proliferation. However, key evidence linking this trans-localization to PH domain-mediated CL binding has been missing. In this study, we demonstrate that p210-PH translocates to mitochondria following cyanide m-chlorophenylhydrazone-induced mitochondrial damage, whereas an R726A mutant deficient in CL binding does not, indicating that the PH domain is sufficient for mitochondrial targeting. Moreover, gene-knockdown of cardiolipin synthase 1, which substantially reduces total CL levels, including three major molecular species, significantly suppresses the mitochondrial localization of both p210 BCR-ABL and p210-PH. These findings establish that the PH domain-CL interaction mediates p210 BCR-ABL translocation to mitochondria, and underscore a pivotal role for CL in CML cell proliferation.