Does mitsugumin 23 play a role in doxorubicin-induced cardiotoxicity?

The main non-malignant cause of death in cancer survivors is heart disease caused by side effects from many chemotherapy agents, including anthracycline doxorubicin. Approximately 1-in-10 cancer survivors suffer irreversible heart damage, but the cause remains unknown. We have recently suggested that Mitsugumin 23 (MG23) is a Ca2+-leak channel located in sarcoplasmic reticulum (SR) membranes (Reilly-O’Donnell et al., 2017). Leakage of Ca2+ from SR stores is a hallmark of heart failure (Bers, 2014). We hypothesize that doxorubicin modulates MG23 resulting in Ca2+ cycle dysfunction. To study the impact of doxorubicin on intrinsic Ca2+ cycling, cardiomyocytes were isolated from wild type (WT) and MG23 knockout (KO) mice using a Langendorff-free method (Ackers-Johnson et al., 2016). Cells were treated with 2.5 µM doxorubicin for 24 hours, cells were loaded with 2 µM Fluo-4 and SR Ca2+ store levels assessed by the addition of 10 mM caffeine. Doxorubicin reduced SR Ca2+ store levels in cardiomyocytes isolated from both WT and MG23 KO mice but had a markedly greater effect on store levels in WT cells. To investigate the direct effect of doxorubicin on MG23 channel function we incorporated mouse cardiac SR vesicles into artificial bilayers under voltage-clamp conditions (Pitt et al., 2010). We show that luminal addition of doxorubicin to MG23 increases channel activity. Human model translation was assessed by demonstrating that doxorubicin increased the activity of recombinant human MG23 channels. This work implicates MG23 as a potential new therapeutic target in the treatment of cardiac dysfunction as a side effect of anthracycline chemotherapies.