Mitsugumin 23 is a putative zinc regulated sarcoplasmic reticulum calcium leak channel
Abstract
Cardiac ion homeostasis is vital for efficient cardiac function. Intracellular Ca²⁺ dyshomeostasis and sarcoplasmic reticulum (SR) Ca²⁺ leak are considered hallmarks of heart failure. Disrupted intracellular Zn²⁺ signalling is also prevalent in heart failure, with raised Zn²⁺ levels observed in cardiomyocytes under ischaemic conditions. Adverse effects of elevated Zn²⁺ levels on cardiac function are widely reported, including reduced contractile force and aberrant Ca²⁺ handling.
The molecular mechanisms linking dysregulated Zn²⁺ and Ca²⁺ signalling remain poorly understood. MG23 is a newly identified, Ca²⁺-permeable cation channel located on the SR/endoplasmic reticulum. Recently, the activity of MG23 was shown to be modulated by pathological [Zn²⁺].
The aim of this project was to investigate the role of MG23 as a Zn²⁺-regulated Ca²⁺ leak channel and to determine how altered [Zn²⁺] shapes intracellular Ca²⁺ dynamics.
Using isolated mouse cardiomyocytes, this study showed that MG23 protein expression increased following hypoxia (≤ 1% O₂; 3-24 hours). Live cell imaging demonstrated that intracellular Zn²⁺ levels are elevated in cells exposed to hypoxia, coinciding with a significant reduction in SR Ca²⁺ levels. Decreased SR Ca²⁺ was not observed following treatment with Zn²⁺-chelator TPEN at early hypoxic time points (3 hours). Strikingly, decreased SR Ca²⁺ content was not observed in cardiomyocytes isolated from Mg23-KO hearts until 24 hours hypoxia. This provides the first evidence that MG23 activity is regulated by Zn²⁺ leading to increased SR Ca²⁺ leak.
In heart failure, intracellular [Zn²⁺] is elevated to levels that increase MG23 activity. This study reveals that Zn²⁺ modulation of MG23 occurs across multiple species including mouse and human. Glutamic acid residue 79 in human MG23 was identified as a potential site for controlling Zn²⁺ modulation of channel activity. MG23 may therefore be a novel target in the design of therapeutic interventions for treatment of heart failure where SR Ca²⁺ leak is exacerbated.
Type
Thesis, PhD Doctor of Philosophy
Rights
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
Embargo Date: 2026-11-05
Embargo Reason: Thesis restricted in accordance with University regulations. Print and electronic copy restricted until 5th November 2026
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