Cellular zinc is at the heart of sarcoplasmic reticulum calcium leak in cardiac muscle

In the failing heart, calcium cycling is profoundly altered leading to leak of calcium from the sarcoplasmic reticulum (SR). This results in impaired contraction of cardiac tissue and fatal cardiac arrhythmias. The underlying molecular mechanisms governing this leak are unclear.

Disrupted zinc-homeostasis is linked to dysregulated intracellular calcium responses but the relationship between SR calcium leak and cellular zinc dyshomeostasis has never been investigated. Mitsugumin 23 (MG23) is a newly identified SR located ion channel that displays calcium-handling properties.

We have recently shown that MG23 is regulated by zinc and suggest that dysregulation of cellular zinc levels is a key driver of irregular MG23 channel activity that is likely to result in diastolic SR calcium leak.

The aim of this study is to investigate the role of MG23 as a major SR calcium leak channel, to define the contribution of MG23 in deleterious calcium cycling in diastole, and to define the role of cellular zinc in shaping calcium dynamics in the heart.

The outputs of this work will advance understanding of the intrinsic relationship between cardiac cellular zinc and calcium dynamics, and highlight MG23 as a new therapeutic target in cardiac dysfunction.