Palmitic acid (PA), the most abundant saturated fatty acid (SFA) in humans, plays a key role in energy metabolism, membrane synthesis, and signaling. Oligodendrocyte precursor cells (OPCs), which generate mature oligodendrocytes (OLs) forming the myelin sheath, are responsive to metabolic and redox signals. Despite increasing interest in lipid metabolism and mitochondrial dynamics as regulators of OPC fate, the effects of PA remain unclear. This study investigates the biphasic, dose-dependent effects of PA on OPCs using the oligodendrocyte precursor MO3.13 cell line and employs rat organotypic slice cultures to evaluate the effects of non-toxic PA doses under pathological conditions and on axonal (re)-myelination. In MO3.13 cells, high-dose PA (100 µM) induces mitochondrial fragmentation and caspase-7 activation, accompanied by reduced mitofusin-2 (MFN2) and phosphorylated dynamin-related protein 1 at Ser616 (p-DRP1), indicating altered fusion-fission balance and impaired reactive oxygen species (ROS) generation. In contrast, low-dose PA (25 µM) triggers a protective response involving nuclear factor erythroid 2-related factor 2 (Nrf2) activation and upregulation of antioxidant and lipid-regulatory genes (glutamate-cysteine ligase modifier subunit [GCLM], NAD(P)H dehydrogenase [quinone] 1 [NQO1], peroxisome proliferator-activated receptor gamma [PPARγ], and cluster of differentiation 36 [CD36]) resulting in reduced intracellular ROS and enhanced lipid mobilization. PA 25 µM promotes OPC differentiation by inhibiting migration and cell cycle progression and increasing myelin basic protein (MBP) and proteolipid protein (PLP) expression. Notably, early exposure (1 day) favors mitochondrial fusion, whereas prolonged exposure (4 days) shows a physiological shift to fission. PA 25 µM prevents neurodegeneration in hippocampal organotypic slice cultures exposed to a neuroinflammatory insult. In cerebellar organotypic slice cultures, PA 25 µM enhances axonal myelination and accelerates remyelination following lysolecithin-induced demyelination. These findings highlight the physiological relevance of low-dose PA in modulating OLs.

This study evaluated the effect of a nutraceutical supplementation (NS) and Mediterranean hypocaloric diet (MHD) on hepatic steatosis indices (HSIs), γ-glutamyl transferase (γGT), and lipid profile in adults with hyperlipidemia and nonalcoholic fatty liver disease (NAFLD). In vitro study on HepG2 cells explored potential molecular mechanisms. A retrospective study was conducted on 45 overweight/obese subjects (19 M) prescribed MHD with/without NS. Anthropometric data, biochemical parameters, HSIs, and γGT were collected at baseline and after 3 months. In vitro, cells were pretreated with single and mixed NS components and then with tumor necrosis factor α (TNFα) or fatty acids (FAs). Antioxidant and antiinflammatory activities were evaluated by fluorescence assays and quantitative polymerase chain reaction or enzyme-linked immunosorbent assay; antiapoptotic effects by Western blot. After 3 months, all subjects improved anthropometric and biochemical parameters but only the combined MHD and NS treatment significantly reduced insulin resistance, HSIs, low-density lipoprotein cholesterol, and γGT. In vitro, treatment with mixed NS components decreased TNFα-/FAs-induced reactive oxygen species. Combined treatment also modulated the inflammatory response by lowering interleukin-6 and interleukin-1β, increasing interleukin-10 and pro-caspase 8 expression. These findings suggest that NS, due to its antiinflammatory properties, represents a promising strategy for NAFLD management.

Nutrient availability is fundamental for osteoblasts (OBs) bioenergetics and function. However, OBs metabolic response to glucose (G) restriction and lipid availability remains to be clarified. We studied the effect of G restriction in MC3T3-E1 osteoblastic cells and in primary osteoblasts (pOBs) cultured with G at physiological (PG; 5.5 mM) or low (LG; 1.25 mM) concentrations. We found that LG decreased OBs proliferation, migration, and clonogenicity compared to PG levels, while osteogenesis was enhanced in LG conditions. An increased mitochondrial size associated with increased mitofusin 2 expression and elongated mitochondria in LG was observed compared to PG-treated OBs. These mitochondrial features were associated with increased mitochondrial oxidative capacity and elevated ATP production in LG-treated OBs compared to PG. Etomoxir (Eto) addition to LG negatively affected mitochondrial function and osteogenesis, suggesting lipid utilization by OBs in LG condition. Accordingly, lipid droplet count was lower in LG condition while lipolysis genes were upregulated. Eto addition to lipid-reduced serum induced increased lipid droplets accumulation and downregulation of lipolytic genes in LG environment. Finally, inhibition of lipolysis through ATGListatin reduced osteogenesis in LG-treated compared to PG-treated OBs cell cultures. Altogether, these results show that OBs function is modulated by fuel availability and reinforces the fundamental role for lipid utilization in orchestrating OBs metabolism, during energy demand when tissue glucose availability is limited, such as in pathophysiological conditions, including diabetes.

Chlorogenic acid (CGA), a polyphenol found mainly in coffee and tea, exerts antioxidant, anti-inflammatory and anti-apoptotic effects at the gastrointestinal level. However, although CGA is known to cross the blood–brain barrier (BBB), its effects on the CNS are still unknown. Oligodendrocytes (OLs), the myelin-forming cells in the CNS, are the main target in demyelinating neuroinflammatory diseases such as multiple sclerosis (MS). We evaluated the antioxidant, anti-inflammatory and anti-apoptotic roles of CGA in M03-13, an immortalized human OL cell line. We found that CGA reduces intracellular superoxide ions, mitochondrial reactive oxygen species (ROS) and NADPH oxidases (NOXs) /dual oxidase 2 (DUOX2) protein levels. The stimulation of M03-13 cells with TNFα activates the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kB) pathway, leading to an increase in superoxide ion, NOXs/DUOX2 and phosphorylated extracellular regulated protein kinase (pERK) levels. In addition, tumor necrosis factor alpha (TNF-α) stimulation induces caspase 8 activation and the cleavage of poly-ADP-ribose polymerase (PARP). All these TNFα-induced effects are reversed by CGA. Furthermore, CGA induces a blockade of proliferation, driving cells to differentiation, resulting in increased mRNA levels of myelin basic protein (MBP) and proteolipid protein (PLP), which are major markers of mature OLs. Overall, these data suggest that dietary supplementation with this polyphenol could play an important beneficial role in autoimmune neuroinflammatory diseases such as MS.

Inside the adult CNS, oligodendrocyte progenitor cells (OPCS) are able to proliferate, migrate and differentiate into mature oligodendrocytes (OLs) which are responsible for the production of myelin sheet and energy supply for neurons. Moreover, in demyelinating diseases, OPCs are recruited to the lesion areas where they undergo differentiation and myelin synthesis. Serotonin (5-hydroxytryptamine, 5-HT) is involved in OLs’ development and myelination, but so far the molecular mechanisms involved or the effects of 5-HT on mitochondria function have not yet been well documented. Our data show that 5-HT inhibits migration and proliferation committing cells toward differentiation in an immortalized human oligodendrocyte precursor cell line, M03-13. Migration blockage is mediated by reactive oxygen species (ROS) generation since antioxidants, such as Vit C and Cu-Zn superoxide dismutase, prevent the inhibitory effects of 5-HT on cell migration. 5-HT inhibits OPC migration and proliferation and increases OL phenotypic markers myelin basic protein (MBP) and Olig-2 via protein kinase C (PKC) activation since the inhibitor of PKC, bis-indolyl-maleimide (BIM), counteracts 5-HT effects. NOX inhibitors as well, reverse the effects of 5-HT, indicating that 5-HT influences the maturation process of OPCs by NOX-dependent ROS production. Finally, 5-HT increases mitochondria function and antioxidant activity. The identification of the molecular mechanisms underlying the effects of 5-HT on maturation and energy metabolism of OPCs could pave the way for the development of new treatments for autoimmune demyelinating diseases such as Multiple Sclerosis where oligodendrocytes are the primary target of immune attack.

Energy metabolism and redox state are strictly linked; energy metabolism is a source of reactive oxygen species (ROS) that, in turn, regulate the flux of metabolic pathways. Moreover, to assure redox homeostasis, metabolic pathways and antioxidant systems are often coordinately regulated. Several findings show that superoxide dismutase 1 (SOD1) enzyme has effects that go beyond its superoxide dismutase activity and that its functions are not limited to the intracellular compartment. Indeed, SOD1 is secreted through unconventional secretory pathways, carries out paracrine functions and circulates in the blood bound to lipoproteins. Striking experimental evidence links SOD1 to the redox regulation of metabolism. Important clues are provided by the systemic effects on energy metabolism observed in mutant SOD1-mediated amyotrophic lateral sclerosis (ALS). The purpose of this review is to analyze in detail the involvement of SOD1 in redox regulation of metabolism, nutrient sensing, cholesterol metabolism and regulation of mitochondrial respiration. The scientific literature on the relationship between ALS, mutated SOD1 and metabolism will also be explored, in order to highlight the metabolic functions of SOD1 whose biological role still presents numerous unexplored aspects that deserve further investigation.

OPINION article Front. Cell. Infect. Microbiol., 15 December 2020Sec. Virus and Host Volume 10 - 2020 | https://doi.org/10.3389/fcimb.2020.608435