The [2Fe-2S] protein CISD2 plays a key role in preventing iron accumulation in cardiomyocytes.

Considered a key aging gene, CISD2, encoding CDGSH iron-sulfur domain-containing protein 2, plays a central role in regulating calcium homeostasis, preventing mitochondrial dysfunction, and the activation of autophagy and apoptosis in different cells. Here, we show that cardiomyocytes from CISD2-null mice accumulate high levels of iron and contain high levels of transferrin receptor and ferritin. Using proteomics and transmission electron microscopy, we further show that the lack of CISD2 induces several features of the aging process in young mice, but other features are not induced. Taken together, our findings suggest that CISD2 protects cardiomyocytes from overaccumulation of iron, which is common in aging hearts and can contribute to the pathogenesis of heart failure.