PGAM5-mediated VDAC1 oligomerization facilitates ponatinib-induced cardiotoxicity via disrupting the...

Ponatinib is an effective tyrosine kinase inhibitor for chronic myeloid leukemia with the T315I mutation, but its clinical use is often limited by serious cardiovascular toxicity. Although mitochondrial dysfunction has been implicated in this process, the upstream stress-sensing mechanism that converts ponatinib exposure into collapse of mitochondrial quality control (MQC) remains poorly defined. We therefore investigated whether the PGAM5/VDAC1 axis mediates ponatinib-induced cardiac injury by coordinately disrupting mitophagy and the mitochondrial unfolded protein response (UPR^mt).

Cardiomyocyte-specific PGAM5 knockout mice (Pgam5_cko) and littermate controls (Pgam5_f/f) were fed a high-fat diet and then exposed to ponatinib. Cardiac function and adult cardiomyocyte contractility were assessed by echocardiography and IonOptix analysis. Single-cell RNA sequencing, in vivo genetic loss-of-function models, and HL-1 cells with stable Pgam5 knockdown were used to define the underlying mechanism. MQC status, including mitophagy and UPR^mt, was evaluated by fluorescence imaging, RT-qPCR, western blotting, and biochemical assays.

Ponatinib markedly increased PGAM5 expression in the heart and induced contractile dysfunction, inflammatory activation, and cardiomyocyte apoptosis. These changes were substantially attenuated in Pgam5_cko mice. Mechanistically, ponatinib promoted pathological oligomerization of the outer mitochondrial membrane protein VDAC1 in a PGAM5-dependent manner. This event was accompanied by simultaneous suppression of PINK1/Parkin-related mitophagy and the UPR^mt program, resulting in mitochondrial fragmentation, oxidative stress, and impaired bioenergetic function. At the functional level, loss of PGAM5 restored MQC and preserved cardiac performance under ponatinib stress. Importantly, forced VDAC1 oligomerization with arsenic trioxide largely abolished the protective effects of PGAM5 deficiency, supporting VDAC1 oligomerization as a critical downstream event in this pathway.

These findings identify the PGAM5/VDAC1 axis as a key mechanism linking ponatinib stress to coordinated failure of MQC in the heart. By simultaneously disabling mitophagy and UPR^mt, this pathway drives mitochondrial dysfunction and cardiac injury. Targeting PGAM5-dependent VDAC1 oligomerization may therefore represent a potential strategy for limiting ponatinib-associated cardiotoxicity.