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Deficiency of mitochondrial calcium uniporter abrogates iron overload-induced cardiac dysfunction by reducing ferroptosis

Basic Research in Cardiology volume 118, Article number: 21 (2023) Cite this article

Abstract

Iron overload associated cardiac dysfunction remains a significant clinical challenge whose underlying mechanism(s) have yet to be defined. We aim to evaluate the involvement of the mitochondrial Ca2+ uniporter (MCU) in cardiac dysfunction and determine its role in the occurrence of ferroptosis. Iron overload was established in control (MCUfl/fl) and conditional MCU knockout (MCUfl/fl-MCM) mice. LV function was reduced by chronic iron loading in MCUfl/fl mice, but not in MCUfl/fl-MCM mice. The level of mitochondrial iron and reactive oxygen species were increased and mitochondrial membrane potential and spare respiratory capacity (SRC) were reduced in MCUfl/fl cardiomyocytes, but not in MCUfl/fl-MCM cardiomyocytes. After iron loading, lipid oxidation levels were increased in MCUfl/fl, but not in MCUfl/fl-MCM hearts. Ferrostatin-1, a selective ferroptosis inhibitor, reduced lipid peroxidation and maintained LV function in vivo after chronic iron treatment in MCUfl/fl hearts. Isolated cardiomyocytes from MCUfl/fl mice demonstrated ferroptosis after acute iron treatment. Moreover, Ca2+ transient amplitude and cell contractility were both significantly reduced in isolated cardiomyocytes from chronically Fe treated MCUfl/fl hearts. However, ferroptosis was not induced in cardiomyocytes from MCUfl/fl-MCM hearts nor was there a reduction in Ca2+ transient amplitude or cardiomyocyte contractility. We conclude that mitochondrial iron uptake is dependent on MCU, which plays an essential role in causing mitochondrial dysfunction and ferroptosis under iron overload conditions in the heart. Cardiac-specific deficiency of MCU prevents the development of ferroptosis and iron overload-induced cardiac dysfunction.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article and supplementary materials. Raw data can be made available on reasonable request.

Abbreviations

ECG:

Electrocardiography

ECHO:

Echocardiography

Fer-1:

Ferrostatin-1

GPX4:

Glutathione peroxidase 4

LVEF:

Left ventricular ejection fraction

LVFS:

Left ventricular fractional shortening

LV:

Left ventricle

MCU:

Mitochondrial calcium uniporter

OCR:

Oxygen consumption rate

SRC:

Spare respiratory capacity

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Acknowledgements

We thank Professor Jeffery Molkentin for kindly providing the MCUfl/fl and MCUfl/fl-MCM breeding pairs.

Funding

This work was supported by the National Institutes of Health (R01s HL157116 to LHX and JKG and HL133294 to LHX), the American Heart Association (19TPA34900003 to LHX and JKG), and the National Science and Technology Development Agency Thailand (to NC), the National Research Council of Thailand (N42A660301 to SCC), the Thailand Research Fund-Royal Golden Jubilee Program (to SW and NC), and the Prince Mahidol Award Foundation (to NS).

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Authors and Affiliations

  1. Department of Cell Biology and Molecular Medicine, Rutgers University-New Jersey Medical School, Newark, NJ, 07103, USA

    Nadezhda Fefelova, Suwakon Wongjaikam, Sri Harika Pamarthi, Natthaphat Siri-Angkul, Thomas Comollo, Andreas Ivessa, Judith K. Gwathmey & Lai-Hua Xie

  2. Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

    Suwakon Wongjaikam, Natthaphat Siri-Angkul, Siriporn C. Chattipakorn & Nipon Chattipakorn

  3. Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

    Suwakon Wongjaikam, Natthaphat Siri-Angkul & Nipon Chattipakorn

  4. Department of Physiology, University of Maryland, Baltimore, MD, USA

    Anshu Kumari & Vivek Garg

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  1. Nadezhda Fefelova
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Correspondence to Lai-Hua Xie.

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This article is part of the topical collection “Mitochondria at the heart of cardioprotection”.

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Fefelova, N., Wongjaikam, S., Pamarthi, S.H. et al. Deficiency of mitochondrial calcium uniporter abrogates iron overload-induced cardiac dysfunction by reducing ferroptosis. Basic Res Cardiol 118, 21 (2023). https://doi.org/10.1007/s00395-023-00990-7

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