Changes in the Stoichiometry of Uniplex Decrease Mitochondrial Calcium Overload and Contribute to Tolerance of Cardiac Ischemia/Reperfusion Injury in Hypothyroidism

Abstract

Background: Thyroid hormone status in hypothyroidism (HT) downregulates key elements in Ca2+ handling within the heart, reducing contractility, impairing the basal energetic balance, and increasing the risk of cardiovascular disease. Mitochondrial Ca2+ transport is reduced in HT, and tolerance to reperfusion damage has been documented, but the precise mechanism is not well understood. Therefore, we aimed to determine the stoichiometry and activity of the mitochondrial Ca2+ uniporter or uniplex in an HT model and the relevance to the opening of the mitochondrial permeability transition pores (mPTP) during ischemia/reperfusion (I/R) injury.Methods: An HT model was established in Wistar rats by treatment with 6-propylthiouracil for 28 days. Uniplex composition and activity were determined in cardiac mitochondria. Hearts were perfused ex vivo to induce I/R injury, and functional parameters related to contractility and tissue viability were evaluated.Results: The cardiac stoichiometry between two subunits of the uniplex (MICU1/MCU) increased by 25% in animals with HT. The intramitochondrial Ca2+ content was reduced by 40% and was less prone to the mPTP opening. After I/R injury, ischemic contracture and the onset of ventricular fibrillation were delayed in animals with HT, concomitant with a reduction in oxidative damage and mitochondrial dysfunction.Conclusions: Our results suggest that HT is associated with an increase in the cardiac MICU1/MCU ratio, thereby changing the stoichiometry between these subunits to increase the threshold to cytosolic Ca2+ and reduce mitochondrial Ca2+ overload. Our results also demonstrate that this HT model can be used to explore the role of mitochondrial Ca2+ transport in cardiac diseases due to its induced tolerance to cardiac damage.

Asymmetric Opening of Mitochondrial Permeability Transition Pore in Mouse Brain Hemispheres: A Link to the Mitochondrial Calcium Uniporter Complex

“…Alteration of MICU1/2 expression and dysfunction, for example, cause dysregulation of mitochondrial Ca 2+ homeostasis, leading to disease-associated cell damage (Mammucari, Gherardi, Rizzuto, 2017). Moreover, variable mitochondrial Ca 2+ uptake mechanisms and mPTP opening have also been proposed to be a result of the differential stoichiometry of the MCUC subunits (Chapoy-Villanueva et al, 2019;Paillard et al, 2017). However, contrary to these studies, our data from the mouse brain hemispheres show no noticeable difference in the expression of Micu1, Micu2, and Mcub mRNA.…”

MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth

“…A recent study has demonstrated that alternations in the stoichiometry of MCU complexes causes a change in the Ca 2+ influx into the mitochondria. 28 Furthermore, Julia et al reported that the MICU1 functions as a gatekeeper to inhibit mitochondrial Ca 2+ overload. 29 Our data indicated that the mRNA expression of MICU1, but not other members of the MCU complex is downregulated in CRC tissues, suggesting that MICU1 may function together with MCU to regulate the level of mitochondrial Ca 2+ in CRC cells.…”

Therapeutic Applications of Cannabinoids in Cardiomyopathy and Heart Failure

“…Interestingly, CBD can antagonize the activation of the GPR55 receptor [23], avoiding IP 3dependent Ca 2+ liberation from the sarcoplasmic reticulum, limiting the entry of Ca 2+ into the mitochondria during ischemia/reperfusion, and preventing further injury caused by the overflow of Ca 2+ . In this sense, avoiding mitochondrial Ca 2+ overload has been established as a paradigm of cardioprotection in cardiac ischemia/reperfusion injury [47,48].…”