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

Cells. 2023 Mar 29;12(7):1042. doi: 10.3390/cells12071042.

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.

Keywords: antioxidants; cardiomyocyte; lipotoxicity; peptides; selenoproteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Fatty Acids / metabolism
  • Mitochondria / metabolism
  • Myocytes, Cardiac* / metabolism
  • Oxidative Stress
  • Palmitates* / metabolism
  • Palmitates* / toxicity

Substances

  • Palmitates
  • Fatty Acids

Grants and funding

This research was funded by the Ministry of Education, Universities and Research (MIUR) of Italy [project Proof of concept- grant number POC01_00049–“Il dominio catalitico 43–52 derivato dalla selenoproteina T (PSELT) come nuovo farmaco nella protezione dall’infarto del miocardio”]; the University of Calabria “ex-60%”, The Italian Foundation for Cancer Research (AIRC) under Start-Up 2018–ID. 21651–P.I. Ernestina Marianna De Francesco (EMDF), and The Italian Foundation for Cancer Research (AIRC) under IG24449-P.I. Nicola Amodio (NA).