Palmitate-Induced Cardiac Lipotoxicity Is Relieved by the Redox-Active Motif of SELENOT through Improving Mitochondrial Function and Regulating Metabolic State

Author:

Rocca Carmine1ORCID,De Bartolo Anna12,Guzzi Rita34ORCID,Crocco Maria Caterina35ORCID,Rago Vittoria6ORCID,Romeo Naomi1,Perrotta Ida7,De Francesco Ernestina Marianna8,Muoio Maria Grazia8,Granieri Maria Concetta1,Pasqua Teresa9,Mazza Rosa1,Boukhzar Loubna2,Lefranc Benjamin210ORCID,Leprince Jérôme210ORCID,Gallo Cantafio Maria Eugenia11,Soda Teresa9ORCID,Amodio Nicola11,Anouar Youssef210ORCID,Angelone Tommaso112ORCID

Affiliation:

1. Cellular and Molecular Cardiovascular Pathophysiology Laboratory, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, 87036 Rende, Italy

2. UNIROUEN, Inserm U1239, Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Rouen Normandie University, 76000 Mont-Saint-Aignan, France

3. Department of Physics, Molecular Biophysics Laboratory, University of Calabria, 87036 Rende, Italy

4. CNR-NANOTEC, Department of Physics, University of Calabria, 87036 Rende, Italy

5. STAR Research Infrastructure, University of Calabria, Via Tito Flavio, 87036 Rende, Italy

6. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy

7. Centre for Microscopy and Microanalysis (CM2), Department of Biology, Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, 87036 Rende, Italy

8. Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95124 Catania, Italy

9. Department of Health Science, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy

10. UNIROUEN, UMS-UAR HERACLES, PRIMACEN, Cell Imaging Platform of Normandy, Institute for Research and Innovation in Biomedicine (IRIB), 76183 Rouen, France

11. Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy

12. National Institute of Cardiovascular Research (INRC), 40126 Bologna, Italy

Abstract

Cardiac lipotoxicity is an important contributor to cardiovascular complications during obesity. Given the fundamental role of the endoplasmic reticulum (ER)-resident Selenoprotein T (SELENOT) for cardiomyocyte differentiation and protection and for the regulation of glucose metabolism, we took advantage of a small peptide (PSELT), derived from the SELENOT redox-active motif, to uncover the mechanisms through which PSELT could protect cardiomyocytes against lipotoxicity. To this aim, we modeled cardiac lipotoxicity by exposing H9c2 cardiomyocytes to palmitate (PA). The results showed that PSELT counteracted PA-induced cell death, lactate dehydrogenase release, and the accumulation of intracellular lipid droplets, while an inert form of the peptide (I-PSELT) lacking selenocysteine was not active against PA-induced cardiomyocyte death. Mechanistically, PSELT counteracted PA-induced cytosolic and mitochondrial oxidative stress and rescued SELENOT expression that was downregulated by PA through FAT/CD36 (cluster of differentiation 36/fatty acid translocase), the main transporter of fatty acids in the heart. Immunofluorescence analysis indicated that PSELT also relieved the PA-dependent increase in CD36 expression, while in SELENOT-deficient cardiomyocytes, PA exacerbated cell death, which was not mitigated by exogenous PSELT. On the other hand, PSELT improved mitochondrial respiration during PA treatment and regulated mitochondrial biogenesis and dynamics, preventing the PA-provoked decrease in PGC1-α and increase in DRP-1 and OPA-1. These findings were corroborated by transmission electron microscopy (TEM), revealing that PSELT improved the cardiomyocyte and mitochondrial ultrastructures and restored the ER network. Spectroscopic characterization indicated that PSELT significantly attenuated infrared spectral-related macromolecular changes (i.e., content of lipids, proteins, nucleic acids, and carbohydrates) and also prevented the decrease in membrane fluidity induced by PA. Our findings further delineate the biological significance of SELENOT in cardiomyocytes and indicate the potential of its mimetic PSELT as a protective agent for counteracting cardiac lipotoxicity.

Funder

Ministry of Education, Universities and Research

University of Calabria

The Italian Foundation for Cancer Research

Ernestina Marianna De Francesco

Publisher

MDPI AG

Subject

General Medicine

Reference85 articles.

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