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The protective effect of docosahexaenoic acid on mitochondria in a SH-SY5Y model of rotenone-induced toxicity

ABSTRACT: Polyunsaturated fatty acids in particular omega-3 fatty acids, such as docosahexaenoic acid (DHA) are essential nutrients and components of the plasma membrane. They are involved in various processes, among them synaptic development, functionality, integrity and plasticity and are therefore thought to have general neuroprotective properties. Considerable research evidence further supports beneficial effects of omega-3 fatty acids specifically on mitochondrial structure and function through their antioxidant and anti-apoptotic properties, which makes it an attractive addition in treatment options for neurodegenerative disorders, in which mitochondrial alterations are commonly observed. However, so far precise information on the underlying protective mechanisms are still lacking. Thus in this study, we utilized the most common neuronal cell line (SH-SY5Y) and induced mitochondrial oxidative stress through the addition of rotenone. To study the potential protective effect of DHA, cells were additionally pre-treated with DHA prior rotenone administration. By combining SILAC labelling, mitochondria enrichment, and subsequent proteomic analyses, we aimed to determine the capacity of DHA to alleviate mitochondrial oxidative stress in vitro and further shed light on molecular mechanisms contributing to the proposed neuroprotective effect. Indeed we confirmed a general increase in intensity of mitochondrial proteins in DHA pre-treated cells. Furthermore, we were able to define a compensatory mechanism by which the inhibition of complex I is overcome by an increased activity of the fatty acid beta oxidation in response to DHA pre-treatment.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Neuron Associated Cell

SUBMITTER: Britta Eggers

LAB HEAD: Katrin Marcus

PROVIDER: PXD049302 | Pride | 2025-02-24

REPOSITORIES: pride

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The Protective Effect of Docosahexaenoic Acid on Mitochondria in SH-SY5Y Model of Rotenone-Induced Toxicity.

Eggers Britta B Stepien Jennifer J Reker Anne-Katrin AK Esser Svenja S Pfeiffer Kathy K Pawlas Magdalena M Barkovits Katalin K Marcus Katrin K

Metabolites 20250108 1

<b>Background:</b> Polyunsaturated fatty acids in particular omega-3 fatty acids, such as docosahexaenoic acid (DHA), are essential nutrients and components of the plasma membrane. They are involved in various processes, including synaptic development, functionality, integrity, and plasticity, and are therefore thought to have general neuroprotective properties. Considerable research evidence further supports the beneficial effects of omega-3 fatty acids, specifically on mitochondria, through th ...[more]

PMID: 39852372

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Project description:Background: Docosahexaenoic acid (DHA) is a natural compound with anticancer and anti-angiogenesis activity that is currently under investigation as both a preventative agent and an adjuvant to breast cancer therapy. However, the precise mechanisms of DHA’s anticancer activities are unclear. It is understood that the intercommunication between cancer cells and their microenvironment is essential to tumor angiogenesis. Exosomes are extracellular vesicles that are important mediators of intercellular communication and play a role in promoting angiogenesis. However, very little is known about the contribution of breast cancer exosomes to tumor angiogenesis or whether exosomes can mediate DHA’s anticancer action. Results: Exosomes were collected from MCF7 and MDA-MB-231 breast cancer cells after treatment with DHA. We observed an increase in exosome secretion and exosome microRNA contents from the DHA-treated cells. The expression of 83 microRNAs in the MCF7 exosomes was altered by DHA (>2-fold). The most abundant exosome microRNAs (let-7a, miR-23b, miR-27a/b, miR-21, let-7, and miR-320b) are known to have anti-cancer and/or anti-angiogenic activity. These microRNAs were also increased by DHA treatment in the exosomes from other breast cancer lines (MDA-MB-231, ZR751 and BT20), but not in exosomes from normal breast cells (MCF10A). When DHA-treated MCF7 cells were co-cultured with or their exosomes were directly applied to endothelial cell cultures, we observed an increase in the expression of these microRNAs in the endothelial cells. Furthermore, overexpression of miR-23b and miR-320b in endothelial cells decreased the expression of their pro-angiogenic target genes (PLAU, AMOTL1, NRP1 and ETS2) and significantly inhibited tube formation by endothelial cells, suggesting that the microRNAs transferred by exosomes mediate DHA’s anti-angiogenic action. These effects could be reversed by knockdown of the Rab GTPase, Rab27A, which controls exosome release. Conclusions: We conclude that DHA alters breast cancer exosome secretion and microRNA contents, which leads to the inhibition of angiogenesis. Our data demonstrate that breast cancer exosome signaling can be targeted to inhibit tumor angiogenesis and provide new insight into DHA’s anticancer action, further supporting its use in cancer therapy. Examination of small RNA populations in MCF7 cells and exosomes after DHA treatment.

Project description:Fish oil supplementation is generally seen as beneficial for human health, due to the presence of n-3 polyunsaturated fatty acids (n-3 PUFAs). These fatty acids can elicit their effect through changes in gene expression. Effects of n-3 PUFAs on gene expression of inflammatory and atherogenic markers have been shown in several in vitro and animal studies. However, little evidence is available on human in vivo studies on n-3 PUFA related gene expression. In the present study we investigate the effects of EPA and DHA supplementation for 6 months on gene expression profiles of peripheral blood mononuclear cells (PBMCs). Whole genome microarray analysis was performed on PBMC RNA from subjects who received 1.8 grams of EPA and DHA in capsules (n=23) or capsules containing high oleic acid sunflower oil (HOSF)(n=25). Intake of EPA and DHA resulted in a change of 1040 genes. We found a down-regulation in inflammatory and atherogenic related pathways, such as NF-ÎºB signaling, eicosanoid synthesis, scavenger receptors activity and cell adhesion. These results seem to point to an improvement in health status, in which lymphocytes are less prone to produce chemokines and adhesion molecules and monocytes show reduced susceptibility to differentiate into foam cells. Overall, beneficial effects of n-3 PUFAs that have been described in vitro and in animal studies, were shown in vivo in human subjects in this study. This not only confirms that EPA and DHA elicits beneficial effects on inflammatory and atherogenic processes of elderly subjects, but also shows that PBMC gene expression profiles can be used to show effects of nutrition on human health status. Fasting venous blood samples were collected at baseline and after 26 weeks of supplementation with either 1.8 g EPA and DHA or HOSF. 4 ml blood was collected for PBMC isolation, using BD Vacutainer Cell Preparation Tubes with sodium citrate (BD, Breda, The Netherlands). Immediately after blood collection PBMCs were isolated according to the manufacturerâs manual. PBMC RNA was isolated from all PBMC samples using Qiagen RNeasy Micro kit (Qiagen, Venlo, the Netherlands). Total RNA from PBMCs from 48 subjects was labeled using a one-cycle cDNA labeling kit (MessageAmpTM II-Biotin Enhanced Kit, Ambion, Inc.) and hybridized to custom designed NuGO GeneChip arrays.

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