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Identification of a mechanism promoting mitochondrial sterol accumulation during myocardial ischemia–reperfusion: role of TSPO and STAR

  • Mitochondria at the heart of cardioprotection
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Abstract

Hypercholesterolemia is a major risk factor for coronary artery diseases and cardiac ischemic events. Cholesterol per se could also have negative effects on the myocardium, independently from hypercholesterolemia. Previously, we reported that myocardial ischemia–reperfusion induces a deleterious build-up of mitochondrial cholesterol and oxysterols, which is potentiated by hypercholesterolemia and prevented by translocator protein (TSPO) ligands. Here, we studied the mechanism by which sterols accumulate in cardiac mitochondria and promote mitochondrial dysfunction. We performed myocardial ischemia–reperfusion in rats to evaluate mitochondrial function, TSPO, and steroidogenic acute regulatory protein (STAR) levels and the related mitochondrial concentrations of sterols. Rats were treated with the cholesterol synthesis inhibitor pravastatin or the TSPO ligand 4’-chlorodiazepam. We used Tspo deleted rats, which were phenotypically characterized. Inhibition of cholesterol synthesis reduced mitochondrial sterol accumulation and protected mitochondria during myocardial ischemia–reperfusion. We found that cardiac mitochondrial sterol accumulation is the consequence of enhanced influx of cholesterol and not of the inhibition of its mitochondrial metabolism during ischemia–reperfusion. Mitochondrial cholesterol accumulation at reperfusion was related to an increase in mitochondrial STAR but not to changes in TSPO levels. 4’-Chlorodiazepam inhibited this mechanism and prevented mitochondrial sterol accumulation and mitochondrial ischemia–reperfusion injury, underlying the close cooperation between STAR and TSPO. Conversely, Tspo deletion, which did not alter cardiac phenotype, abolished the effects of 4’-chlorodiazepam. This study reveals a novel mitochondrial interaction between TSPO and STAR to promote cholesterol and deleterious sterol mitochondrial accumulation during myocardial ischemia–reperfusion. This interaction regulates mitochondrial homeostasis and plays a key role during mitochondrial injury.

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Data availability

Data are available from the corresponding author on reasonable request.

Abbreviations

CYP:

Cytochrome P450

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

SOD2:

Superoxide dismutase 2

COX-IV:

Cytochrome C oxidase

TSPO:

Translocator protein

STAR:

Steroidogenic acute regulatory protein

mPTP:

Mitochondrial permeability transition pore

VDAC:

Voltage-dependent anion channel

ROS:

Reactive oxygen species

AUC:

Area under the curve

AOC:

Area over curve

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Acknowledgements

The authors thank Pr V Papadopoulos (University of Southern California, USA) for providing two pairs of heterozyte TSPO deleted rats, which allowed us to develop a colony. The authors also thank him for helpful advices concerning the synthesis and the use of the fluorescent probe cholesterol-resorufin and for rereading the manuscript. The authors are greatly indebted to the Plateforme de Biochimie du Centre de Recherche sur l’Inflammation (Hopital Bichat, Paris, France) for blood analyses. The authors thank the Imagery platform of IMRB for histological samples preparation and the Animal Facility of IMRB for animal care. The authors also thank Lucien Sambin and Alain Bizé for their help during echocardiographic exams.

Funding

This work was supported by the Fondation de France [Grant No. 2018-00086493]. Juliette Bréhat and Julien Musman were supported by doctoral grants from the Ministère de l’enseignement Supérieur, de la Recherche et de l’Innovation [Grant No. 2013-141, 2018-057].

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Author notes

  1. Juliette Bréhat and Shirin Leick have contributed equally to this work.

Authors and Affiliations

  1. INSERM U955-IMRB, Team Ghaleh, UPEC, Ecole Nationale Vétérinaire d’Alfort, Faculté de Santé, 8 rue du général Sarrail, 94000, Créteil, France

    Juliette Bréhat, Shirin Leick, Julien Musman, Jin Bo Su, Bijan Ghaleh, Sandrine Pons & Didier Morin

  2. CHIV, Villeneuve-Saint-Georges, France

    Nicolas Eychenne

  3. Pôle Biologie-Pathologie, IMRB U955, Hôpital Henri Mondor, Créteil, France

    Frank Giton

  4. CNRS, ICMPE, UMR 7182, UPEC, Thiais, France

    Michael Rivard & Louis-Antoine Barel

  5. Laboratory of Clinical Chemistry, ASST-Brianza Department of Medicine and Surgery, Hospital Pio XI Desio, University of Milano Bicocca, Monza, Italy

    Chiara Tropeano, Frederica Vitarelli & Valerio Leoni

  6. Unit of Medical Genetics and Neurogenetics, Istituto Neurologico Carlo Besta, Fondazione IRCCS, Milan, Italy

    Claudio Caccia

Authors
  1. Juliette Bréhat
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  2. Shirin Leick
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Contributions

VL, MR, SP, BG, and DM contributed to the experimental design; JB, SL, JM, JBS, NE, FG, LAB, CT, FV, CC, and DM conducted the experiments; JB, SL, JM, SP, and DM performed data analysis; SP, BG and DM wrote or contributed to the writing of the manuscript with input from all co-authors. All authors have read and approved the content, and agreed to submit for consideration for publication in the journal.

Corresponding author

Correspondence to Didier Morin.

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Conflict of interests

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethics approval

All animal procedures used in this study were conformed to the Directives of the European Parliament (2010/63/EU-848 EEC). The experimental protocols were reviewed and approved (APAFIS13504#-201820130912402v3 and APAFIS#23908–2020012712028279 v4) by the local Ethic Committee Cometh (Afssa/ENVA/UPEC, N° 16).

Additional information

This article is part of the special issue "Mitochondria at the heart of cardioprotection".

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Bréhat, J., Leick, S., Musman, J. et al. Identification of a mechanism promoting mitochondrial sterol accumulation during myocardial ischemia–reperfusion: role of TSPO and STAR. Basic Res Cardiol (2024). https://doi.org/10.1007/s00395-024-01043-3

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  • DOI: https://doi.org/10.1007/s00395-024-01043-3

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