Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of upper and lower motor neurons leading to muscle paralysis and death. While a link between dysregulated lipid metabolism and ...ALS has been proposed, lipidome alterations involved in disease progression are still understudied. Using a rodent model of ALS overexpressing mutant human Cu/Zn-superoxide dismutase gene (SOD1-G93A), we performed a comparative lipidomic analysis in motor cortex and spinal cord tissues of SOD1-G93A and WT rats at asymptomatic (~70 days) and symptomatic stages (~120 days). Interestingly, lipidome alterations in motor cortex were mostly related to age than ALS. In contrast, drastic changes were observed in spinal cord of SOD1-G93A 120d group, including decreased levels of cardiolipin and a 6-fold increase in several cholesteryl esters linked to polyunsaturated fatty acids. Consistent with previous studies, our findings suggest abnormal mitochondria in motor neurons and lipid droplets accumulation in aberrant astrocytes. Although the mechanism leading to cholesteryl esters accumulation remains to be established, we postulate a hypothetical model based on neuroprotection of polyunsaturated fatty acids into lipid droplets in response to increased oxidative stress. Implicated in the pathology of other neurodegenerative diseases, cholesteryl esters appear as attractive targets for further investigations.
Lack of effective treatments for aggressive breast cancer is still a major global health problem. We have previously reported that photodynamic therapy using methylene blue as photosensitizer ...(MB-PDT) massively kills metastatic human breast cancer, marginally affecting healthy cells. In this study, we aimed to unveil the molecular mechanisms behind MB-PDT effectiveness and specificity towards tumor cells. Through lipidomics and biochemical approaches, we demonstrated that MB-PDT efficiency and specificity rely on polyunsaturated fatty acid-enriched membranes and on the better capacity to deal with photo-oxidative damage displayed by non-tumorigenic cells. We found out that, in tumorigenic cells, lysosome membrane permeabilization is accompanied by ferroptosis and/or necroptosis. Our results also pointed at a cross-talk between lysosome-dependent cell death (LDCD) and necroptosis induction after photo-oxidation, and contributed to broaden the understanding of MB-PDT-induced mechanisms and specificity in breast cancer cells. Therefore, we demonstrated that efficient approaches could be designed on the basis of lipid composition and metabolic features for hard-to-treat cancers. The results further reinforce MB-PDT as a therapeutic strategy for highly aggressive human breast cancer cells.
Cholesterol is an essential component of mammalian plasma membranes. Alterations in sterol metabolism or oxidation have been linked to various pathological conditions, including cardiovascular ...diseases, cancer, and neurodegenerative disorders. Unsaturated sterols are vulnerable to oxidation induced by singlet oxygen and other reactive oxygen species. This process yields reactive sterol oxidation products, including hydroperoxides, epoxides as well as aldehydes. These oxysterols, in particular those with high electrophilicity, can modify nucleophilic sites in biomolecules and affect many cellular functions. Here, we review the generation and measurement of reactive sterol oxidation products with emphasis on cholesterol hydroperoxides and aldehyde derivatives (electrophilic oxysterols) and their effects on protein modifications.
Scope
The mechanisms and involvement of uncoupling protein 1 (UCP1) in the protection from obesity and insulin resistance induced by intake of a high‐fat diet rich in omega‐3 (n‐3) fatty acids are ...investigated.
Methods and results
C57BL/6J mice are fed either a low‐fat (control group) or one of two isocaloric high‐fat diets containing either lard (HFD) or fish oil (HFN3) as fat source and evaluated for body weight, adiposity, energy expenditure, glucose homeostasis, and inguinal white and interscapular brown adipose tissue (iWAT and iBAT, respectively) gene expression, lipidome, and mitochondrial bioenergetics. HFN3 intake protected from obesity, glucose and insulin intolerances, and hyperinsulinemia. This is associated with increased energy expenditure, iWAT UCP1 expression, and incorporation of n‐3 eicosapentaenoic and docosahexaenoic fatty acids in iWAT and iBAT triacylglycerol. Importantly, HFN3 is equally effective in reducing body weight gain, adiposity, and glucose intolerance and increasing energy expenditure in wild‐type and UCP1‐deficient mice without recruiting other thermogenic processes in iWAT and iBAT, such as mitochondrial uncoupling and SERCA‐mediated calcium and creatine‐driven substrate cyclings.
Conclusion
Intake of a high‐fat diet rich in omega‐3 fatty acids protects both wild‐type and UCP1‐deficient mice from obesity and insulin resistance by increasing energy expenditure through unknown mechanisms.
Intake of a high‐fat diet (HFD) rich in fish oil is equally effective in reducing body weight gain, adiposity, and glucose intolerance and increasing energy expenditure in wild‐type and UCP1 knockout mice. These findings support the notion that UCP1‐mediated nonshivering thermogenesis may not be involved in the increase in energy expenditure and protection from diet‐induced obesity and glucose intolerance induced by the intake of an HFD rich in omega‐3 fatty acids.
The retina is a notable tissue with high metabolic needs which relies on specialized vascular networks to protect the neural retina while maintaining constant supplies of oxygen, nutrients, and ...dietary essential fatty acids. Here we analyzed the lipidome of the mouse retina under healthy and pathological angiogenesis using the oxygen-induced retinopathy model. By matching lipid profiles to changes in mRNA transcriptome, we identified a lipid signature showing that pathological angiogenesis leads to intense lipid remodeling favoring pathways for neutral lipid synthesis, cholesterol import/export, and lipid droplet formation. Noteworthy, it also shows profound changes in pathways for long-chain fatty acid production, vital for retina homeostasis. The net result is accumulation of large quantities of mead acid, a marker of essential fatty acid deficiency, and a potential marker for retinopathy severity. Thus, our lipid signature might contribute to better understand diseases of the retina that lead to vision impairment or blindness.
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•Integrated lipidomic & transcriptomic study of the oxygen-induced retinopathy (OIR)•OIR increases triglyceride/cholesteryl ester synthesis for lipid droplet formation•Cholesterol import/export pathways are increased in retinopathy•OIR increases retinal n-9 lipids (mead acid), a possible marker of disease severity
Molecular mechanism of behavior; Metabolomics
Metal-deficient Cu,Zn-superoxide dismutase (apo-SOD1) is associated with the formation of SOD1 aggregates that accumulate in ALS disease. The data supplied in this article support the accompanying ...publication showing SOD1 modification and aggregation induced by lipid aldehydes 1. Here, we present the LC-MS/MS dataset on apo-SOD1 modification induced by seven different lipid aldehydes: 4-hydroxy-2-hexenal (HHE), 4-hydroxy-2-nonenal (HNE), 2-hexen-1-al (HEX), 2,4-nonadienal (NON), 2,4-decadienal (DEC) or secosterol aldehydes (SECO-A or SECO-B). Modified protein samples were digested with trypsin and sequenced by a LC coupled to a Q-TOF instrument. Protein sequencing and peptide modification analysis was performed by Mascot 2.6 (Matrix Science) and further validated by manual inspection. Mass spectrometry data (RAW files) obtained in this study have been deposited to MassIVE and the observed peptide-aldehyde adducts can be used in further studies exploring SOD1 modifications in vivo.
Ocean warming is one of the greatest global threats to coral reef ecosystems; it leads to the disruption of the coral–dinoflagellate symbiosis (bleaching) and to nutrient starvation, because corals ...mostly rely on autotrophy (i.e., the supply of photosynthates from the dinoflagellate symbionts) for their energy requirements. Although coral bleaching has been well studied, the early warning signs of bleaching, as well as the capacity of corals to shift from autotrophy to heterotrophy, are still under investigation. In this study, we evaluated the bleaching occurrence of the scleractinian coral Mussismillia harttii and the hydrocoral Millepora alcicornis during a natural thermal stress event, under the 2015–2016 El Niño influence in three reef sites of the South Atlantic. We focused on the link between peroxynitrite (ONOO−) generation and coral bleaching, as ONOO− has been very poorly investigated in corals and never during a natural bleaching event. We also investigated the natural trophic plasticity of the two corals through the use of new lipid biomarkers. The results obtained first demonstrate that ONOO− is linked to the onset and intensity of bleaching in both scleractinian corals and hydrocorals. Indeed, ONOO− concentrations were correlated with bleaching intensity, with the highest levels preceding the highest bleaching intensity. The time lag between bleaching and ONOO− peak was, however, species-specific. In addition, we observed that elevated temperatures forced heterotrophy in scleractinian corals, as Mu. harttii presented high heterotrophic activity 15 to 30 days prior bleaching occurrence. On the contrary, a lower heterotrophic activity was monitored for the hydrocoral Mi. alicornis, which also experienced higher bleaching levels compared to Mu. hartii. Overall, we showed that the levels of ONOO− in coral tissue, combined to the heterotrophic capacity, are two good proxies explaining the intensity of coral bleaching.
Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the ...metabolic adaptation that tumours exploit to counteract phospholipid oxidation
. Here, we identify proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation
, we now show that 7-DHC accumulation confers a robust prosurvival function in cancer cells. Because of its far superior reactivity towards peroxyl radicals, 7-DHC effectively shields (phospho)lipids from autoxidation and subsequent fragmentation. We provide validation in neuroblastoma and Burkitt's lymphoma xenografts where we demonstrate that the accumulation of 7-DHC is capable of inducing a shift towards a ferroptosis-resistant state in these tumours ultimately resulting in a more aggressive phenotype. Conclusively, our findings provide compelling evidence of a yet-unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.
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