Cyclophilin D-mediated regulation of the permeability transition pore is altered in mice lacking the mitochondrial calcium uniporter

Cardiovascular Research
Randi J ParksElizabeth Murphy

Abstract

Knockout (KO) of the mitochondrial Ca2+ uniporter (MCU) in mice abrogates mitochondrial Ca2+ uptake and permeability transition pore (PTP) opening. However, hearts from global MCU-KO mice are not protected from ischaemic injury. We aimed to investigate whether adaptive alterations occur in cell death signalling pathways in the hearts of global MCU-KO mice. First, we examined whether cell death may occur via an upregulation in necroptosis in MCU-KO mice. However, our results show that neither RIP1 inhibition nor RIP3 knockout afford protection against ischaemia-reperfusion injury in MCU-KO as in wildtype (WT) hearts, indicating that the lack of protection cannot be explained by upregulation of necroptosis. Instead, we have identified alterations in cyclophilin D (CypD) signalling in MCU-KO hearts. In the presence of a calcium ionophore, MCU-KO mitochondria take up calcium and do undergo PTP opening. Furthermore, PTP opening in MCU-KO mitochondria has a lower calcium retention capacity (CRC), suggesting that the calcium sensitivity of PTP is higher. Phosphoproteomics identified an increase in phosphorylation of CypD-S42 in MCU-KO. We investigated the interaction of CypD with the putative PTP component ATP synthase and identified ...Continue Reading

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Citations

Dec 19, 2018·Biomolecules·George A Porter, Gisela Beutner
Jun 6, 2019·Journal of Neurochemistry·Enrique Font-BelmonteArsenio Fernández-López
Jan 17, 2020·Circulation Research·Tyler M Bauer, Elizabeth Murphy
Dec 22, 2019·Nature Communications·Nelli MnatsakanyanElizabeth A Jonas
Jul 7, 2020·Frontiers in Physiology·Georgios Amanakis, Elizabeth Murphy
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Oct 10, 2020·Journal of Molecular and Cellular Cardiology·Katalin MártaGyörgy Hajnóczky
Dec 9, 2020·Journal of Molecular and Cellular Cardiology·Brian O'RourkeTing Liu
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