Membrane lipid profile alterations are associated with the metabolic adaptation of the Caco-2 cells to aglycemic nutritional condition.

Cancer cells can adapt their metabolic activity under nutritional hostile conditions in order to ensure both bioenergetics and biosynthetic requirements to survive. In this study, the effect of glucose deprivation on Caco-2 cells bioenergetics activity and putative relationship with membrane lipid changes were investigated. Glucose deprivation induces a metabolic remodeling characterized at mitochondrial level by an increase of oxygen consumption, arising from an improvement of complex II and complex IV activities and an inhibition of complex I activity. This effect is accompanied by changes in cellular membrane phospholipid profile. Caco-2 cells grown under glucose deprivation show higher phosphatidylethanolamine content and decreased phosphatidic acid content. Considering fatty acid profile of all cell phospholipids, glucose deprivation induces a decrease of monounsaturated fatty acid (MUFA) and n-3 polyunsaturated fatty acids (PUFA) simultaneously with an increase of n-6 PUFA, with consequent drop of n-3/n-6 ratio. Additionally, glucose deprivation affects significantly the fatty acid profile of all individual phospholipid classes, reflected by an increase of peroxidability index in zwitterionic phospholipids and a decrease in all anionic phospholipids, including mitochondrial cardiolipin. These data indicate that Caco-2 cells metabolic remodeling induced by glucose deprivation actively involves membrane lipid changes associated with a specific bioenergetics profile which ensure cell survival.

ORP5/8 and MIB/MICOS link ER-mitochondria and intra-mitochondrial contacts for non-vesicular transport of phosphatidylserine.

Mitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the mitochondrial intermembrane space. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that the main physiological localization of the lipid transfer proteins ORP5 and ORP8 is at mitochondria-associated ER membrane (MAM) subdomains, physically linked to the mitochondrial intermembrane space bridging (MIB)/mitochondrial contact sites and cristae junction organizing system (MICOS) complexes that bridge the two mitochondrial membranes. We also show that ORP5/ORP8 mediate non-vesicular transport of phosphatidylserine (PS) lipids from the ER to mitochondria by cooperating with the MIB/MICOS complexes. Overall our study reveals a physical and functional link between ER-mitochondria contacts involved in lipid transfer and intra-mitochondrial membrane contacts maintained by the MIB/MICOS complexes.

Bile Acids: A Communication Channel in the Gut-Brain Axis.

Bile acids are signalling hormones involved in the regulation of several metabolic pathways. The ability of bile acids to bind and signal through their receptors is modulated by the gut microbiome, since the microbiome contributes to the regulation and synthesis of bile acids as well to their physiochemical properties. From the gut, bacteria have been shown to send signals to the central nervous system via their metabolites, thus affecting the behaviour and brain function of the host organism. In the last years it has become increasingly evident that bile acids affect brain function, during normal physiological and pathological conditions. Although bile acids may be synthesized locally in the brain, the majority of brain bile acids are taken up from the systemic circulation. Since the composition of the brain bile acid pool may be regulated by the action of intestinal bacteria, it is possible that bile acids function as a communication bridge between the gut microbiome and the brain. However, little is known about the molecular mechanisms and the physiological roles of bile acids in the central nervous system. The possibility that bile acids may be a direct link between the intestinal microbiome and the brain is also an understudied subject. Here we review the influence of gut bacteria on the bile acid pool composition and properties, as well as striking evidence showing the role of bile acids as neuroactive molecules.

Lipid efflux mechanisms, relation to disease and potential therapeutic aspects.

Lipids are hydrophobic and amphiphilic molecules involved in diverse functions such as membrane structure, energy metabolism, immunity, and signaling. However, altered intra-cellular lipid levels or composition can lead to metabolic and inflammatory dysfunction, as well as lipotoxicity. Thus, intra-cellular lipid homeostasis is tightly regulated by multiple mechanisms. Since most peripheral cells do not catabolize cholesterol, efflux (extra-cellular transport) of cholesterol is vital for lipid homeostasis. Defective efflux contributes to atherosclerotic plaque development, impaired ß-cell insulin secretion, and neuropathology. Of these, defective lipid efflux in macrophages in the arterial walls leading to foam cell and atherosclerotic plaque formation has been the most well studied, likely because a leading global cause of death is cardiovascular disease. Circulating high density lipoprotein particles play critical roles as acceptors of effluxed cellular lipids, suggesting their importance in disease etiology. We review here mechanisms and pathways that modulate lipid efflux, the role of lipid efflux in disease etiology, and therapeutic options aimed at modulating this critical process.

Cardiolipin profile changes are associated to the early synaptic mitochondrial dysfunction in Alzheimer's disease.

Brain mitochondria are fundamental to maintaining healthy functional brains, and their dysfunction is involved in age-related neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we conducted a research on how both non-synaptic and synaptic mitochondrial functions are compromised at an early stage of AD-like pathologies and their correlation with putative changes on membranes lipid profile, using 3 month-old nontransgenic and 3xTg-AD mice, a murine model of experimental AD. Bioenergetic dysfunction in 3xTg-AD brains is evidenced by a decrease of brain ATP levels resulting, essentially, from synaptic mitochondria functionality disruption as indicated by declined respiratory control ratio associated with a 50% decreased complex I activity. Lipidomics studies revealed that synaptic bioenergetic deficit of 3xTg-AD brains is accompanied by alterations in the phospholipid composition of synaptic mitochondrial membranes, detected either in phospholipid class distribution or in the phospholipids molecular profile. Globally, diacyl- and lyso-phosphatidylcholine lipids increase while ethanolamine plasmalogens and cardiolipins content drops in relation to nontransgenic background. However, the main lipidomic mark of 3xTg-AD brains is that cardiolipin cluster-organized profile is lost in synaptic mitochondria due to a decline of the most representative molecular species. In contrast to synaptic mitochondria, results support the idea that non-synaptic mitochondria function is preserved at the age of 3 months. Although the genetically construed 3xTg-AD mouse model does not represent the most prevalent form of AD in humans, the present study provides insights into the earliest biochemical events in AD brain, connecting specific lipidomic changes with synaptic bioenergetic deficit that may contribute to the progressive synapses loss and the neurodegenerative process that characterizes AD.

Age-dependent biochemical dysfunction in skeletal muscle of triple-transgenic mouse model of Alzheimer`s disease.

The emergence of Alzheimer`s disease as a systemic pathology shifted the research paradigm toward a better understanding of the molecular basis of the disease considering the pathophysiological changes in both brain and peripheral tissues. In the present study, we evaluated the impact of disease progression on physiological relevant features of skeletal muscle obtained from 3, 6 and 12 month-old 3xTg-AD mice, a model of Alzheimer`s disease, and respective agematched nonTg mice. Our results showed that skeletal muscle functionality is already affected in 3-month-old 3xTg-AD mice as evidenced by deficient acetylcholinesterase and catalase activities as well as by alterations in fatty acid composition of mitochondrial membranes. Additionally, an age-dependent accumulation of amyloid-ß1-40 peptide occurred in skeletal muscle of 3xTg-AD mice, an effect that preceded bioenergetics mitochondrial dysfunction, which was only detected at 12 months of age, characterized by decreased respiratory control ratio and ADP/O index and by an impairment of complex I activity. HPLC-MS/MS analyses revealed significant changes in phospholipid composition of skeletal muscle tissues from 3xTg-AD mice with 12 months of age when compared with age-matched nonTg mice. Increased levels of lyso-phosphatidylcholine associated with a decrease of phosphatidylcholine molecular species containing arachidonic acid were detected in 3xTg-AD mice, indicating an enhancement of phospholipase A2 activity and skeletal muscle inflammation. Additionally, a decrease of phosphatidylethanolamine plasmalogens content and an increase in phosphatidylinositol levels was observed in 3xTg-AD mice when compared with age-matched nonTg mice. Altogether, these observations suggest that the skeletal muscle of 3xTg-AD mice are more prone to oxidative and inflammatory events.