The [2Fe-2S] protein CISD2 plays a key role in preventing iron accumulation in cardiomyocytes
2Department of Surgery, School of Medicine, University of Missouri, USA
Studies carried out in hearts of transgenic mice revealed that the expression of CISD2 gene declines with ageing (Chen, Y. et.al. 2010). That CISD2 might be associated with age-related heart failure was deduced from observations obtained in CISD2-null mice in which re-expression of CISD2 attenuated age-related defects in cardiac structure and functions (Yeh, C. et.al. 2021). Since repression of CISD2 in various cell models demonstrably affects iron and calcium metabolism leading to increased ROS production and ensuing cell death (Nechushtai, R. et.al. 2020), we aimed at comparing hearts of CISD2-null mice versus normal mice. We found by quantitative Perl’s iron stain that CISD2-null mice accumulated 4X higher levels of iron than age-matched normal mice and likewise relatively higher ferritin levels (using immunoblots and immunohistochemistry) compared to the control: 50% heavy chain and 23% light chain. In addition, CISD2 null mice also showed a significant (50%) increase in cardiac TfR expression compared to normal mice. By comparative proteomic analysis we also observed changes in proteins associated with iron metabolism, including a 3X increased expression of glycogen synthase kinase 3 β (Gsk3β), which might also indicate higher iron uptake via transferrin receptor-mediated endocytosis in CISD2 null mice hearts. Regarding the source of heart abnormalities observed in CISD2 null mice, we tentatively attribute it to excessive iron accumulation and ROS formation with ensuing ferroptosis. In order to corroborate that hypothesis, we intend to assess the effects of a chelator with proven clinical efficacy in sequestering iron accumulated in iron overloaded hearts.