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Sinapine, but not sinapic acid, counteracts mitochondrial oxidative stress in cardiomyocytes.

ABSTRACT: INTRODUCTION:When confronted to stress or pathological conditions, the mitochondria overproduce reactive species that participate in the cellular dysfunction. These organelles are however difficult to target with antioxidants. A feature of mitochondria that can be used for this is the negatively charged compartments they form. Most of mitochondrion-targeting antioxidants are therefore cationic synthetic molecules. Our hypothesis is that such mitochondriotropic traits might also exists in natural molecules. AIM:We tested here whether sinapine, a natural phenolic antioxidant-bearing a permanent positive charge, can target mitochondria to modulate mitochondrial oxidative stress. METHODS:Experiments were performed in-vitro, in-cellulo, ex-vivo, and in-vivo, using cardiac tissue. The sinapic acid -lacking the positively-charged-choline-moiety present in sinapine-was used as a control. Sinapine entry into mitochondria was investigated in-vivo and in cardiomyocytes. We used fluorescent probes to detect cytosolic (H2DCFDA) and mitochondrial (DHR123) oxidative stress on cardiomyocytes induced with either hydrogen peroxide (H2O2) or antimycin A, respectively. Finally, ROS production was measured with DHE 10 min after ischemia-reperfusion (IR) on isolated heart, treated or not with sinapine, sinapic acid or with a known synthetic mitochondrion-targeted antioxidant (mitoTempo). RESULTS:We detected the presence of sinapine within mitochondria in-vitro, after incubation of isolated cardiomyocytes, and in-vivo, after oral treatment. The presence of sinapic acid was not detected in the mitochondria. Both the sinapine and the sinapic acid limited cytosolic oxidative stress in response to H2O2. Only sinapine was able to blunt oxidative stress resulting from antimycin A-induced mtROS. Both mitoTempo and sinapine improved cardiac functional recovery following IR. This was associated with lower ROS production within the cardiac tissue. CONCLUSION:Sinapine, a natural cationic hydrophilic phenol, commonly and substantially found in rapeseed species, effectively (i) enters within the mitochondria, (ii) selectively decreases the level of mitochondrial oxidative stress and, (iii) efficiently limits ROS production during cardiac ischemia-reperfusion.

SUBMITTER: Boulghobra D

PROVIDER: S-EPMC7251366 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Sinapine, but not sinapic acid, counteracts mitochondrial oxidative stress in cardiomyocytes.

Boulghobra Doria D Grillet Pierre-Edouard PE Laguerre Mickaël M Tenon Mathieu M Fauconnier Jérémy J Fança-Berthon Pascale P Reboul Cyril C Cazorla Olivier O

Redox biology 20200519

<h4>Introduction</h4>When confronted to stress or pathological conditions, the mitochondria overproduce reactive species that participate in the cellular dysfunction. These organelles are however difficult to target with antioxidants. A feature of mitochondria that can be used for this is the negatively charged compartments they form. Most of mitochondrion-targeting antioxidants are therefore cationic synthetic molecules. Our hypothesis is that such mitochondriotropic traits might also exists in ...[more]

PMID: 32464499

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Project description:Acetyl-CoA carboxylase 2 plays a crucial role in regulating mitochondrial fatty acid oxidation in cardiomyocytes. Lithium, a monovalent cation known for its cardioprotective potential, has been investigated for its influence on mitochondrial bioenergetics. The present study explored whether lithium modulated acetyl-CoA carboxylase 2 and mitochondrial fatty acid metabolism in cardiomyocytes and the potential therapeutic applications of lithium in alleviating metabolic stress. Mitochondrial bioenergetic function, fatty acid oxidation, reactive oxygen species production, membrane potential and the expression of proteins involved in fatty acid metabolism in H9c2 cardiomyocytes treated with LiCl for 48 h was measured by using a Seahorse extracellular flux analyzer, fluorescence microscopy and western blotting. Small interfering RNA against glucose transporter type 4 was transfected into H9c2 cardiomyocytes for 48 h to induce metabolic stress mimicking insulin resistance. The results revealed that LiCl at a concentration of 0.3 mM (but not at a concentration of 0.1 or 1.0 mM) upregulated the expression of phosphorylated (p-)glycogen synthase kinase-3 beta and downregulated the expression of p-acetyl-CoA carboxylase 2 but did not affect the expression of adenosine monophosphate-activated protein kinase or calcineurin. Cotreatment with TWS119 (8 µM) and LiCl (0.3 mM) downregulated p-acetyl-CoA carboxylase 2 expression to a similar extent as did treatment with TWS119 (8 µM) alone. Moreover, LiCl (0.3 mM) inhibited mitochondrial fatty acid oxidation, improved coupling efficiency and the cellular respiratory control ratio, hindered reactive oxygen species production and proton leakage and restored mitochondrial membrane potential in glucose transporter type 4 knockdown-H9c2 cardiomyocytes. These findings suggested that low therapeutic levels of lithium can downregulate p-acetyl-CoA carboxylase 2, thus reducing mitochondrial fatty acid oxidation and oxidative stress in cardiomyocytes.

Dataset Information

Sinapine, but not sinapic acid, counteracts mitochondrial oxidative stress in cardiomyocytes.

Publications

Sinapine, but not sinapic acid, counteracts mitochondrial oxidative stress in cardiomyocytes.

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