Dataset Information

Sphingolipids and Mitochondrial Dynamic.

ABSTRACT: For decades, sphingolipids have been related to several biological functions such as immune system regulation, cell survival, and proliferation. Recently, it has been reported that sphingolipids could be biomarkers in cancer and in other human disorders such as metabolic diseases. This is evidenced by the biological complexity of the sphingolipids associated with cell type-specific signaling and diverse sphingolipids molecules. As mitochondria dynamics have serious implications in homeostasis, in the present review, we focused on the relationship between sphingolipids, mainly ceramides and sphingosine-1-phosphate, and mitochondrial dynamics directed by fission, fusion, and mitophagy. There is evidence that the balances of ceramides (C18 and C16) and S1P, as well as the location of specific ceramide synthases in mitochondria, have roles in mitophagy and fission with an impact on cell fate and metabolism. However, signaling pathways controlling the sphingolipids metabolism and their location in mitochondria need to be better understood in order to propose new interventions and therapeutic strategies.

SUBMITTER: Fugio LB

PROVIDER: S-EPMC7140523 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Sphingolipids and Mitochondrial Dynamic.

Fugio Lais Brigliadori LB Coeli-Lacchini Fernanda B FB Leopoldino Andréia Machado AM

Cells 20200301 3

For decades, sphingolipids have been related to several biological functions such as immune system regulation, cell survival, and proliferation. Recently, it has been reported that sphingolipids could be biomarkers in cancer and in other human disorders such as metabolic diseases. This is evidenced by the biological complexity of the sphingolipids associated with cell type-specific signaling and diverse sphingolipids molecules. As mitochondria dynamics have serious implications in homeostasis, i ...[more]

PMID: 32121501

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Project description:Insulin resistance is defined as a complex pathological condition of abnormal cellular and metabolic response to insulin. Obesity and consumption of high-fat diet lead to ectopic accumulation of bioactive lipids in insulin-sensitive tissues. Intracellular lipid accumulation is regarded as one of the major factors in the induction of insulin resistance and type 2 diabetes (T2D). A significant number of studies have described the involvement of ceramides and other sphingolipids in the inhibition of insulin-signaling pathway in both skeletal muscles and the liver. Adverse effects of sphingolipid accumulation have recently been linked to the activation of protein kinase Cζ (PKCζ) and protein phosphatase 2A (PP2A), which, in turn, negatively affect phosphorylation of serine/threonine kinase Akt [also known as protein kinase B (PKB)], leading to decreased glucose uptake in skeletal muscles as well as increased gluconeogenesis and glycogenolysis in the liver. Sphingolipids, in addition to their direct impact on the insulin signaling pathway, may be responsible for other negative aspects of diabetes, namely mitochondrial dysfunction and deficiency. Mitochondrial health, which is characterized by appropriate mitochondrial quantity, oxidative capacity, controlled oxidative stress, undisturbed respiratory chain function, adenosine triphosphate (ATP) production and mitochondrial proliferation through fission and fusion, is impaired in the skeletal muscles and liver of T2D subjects. Recent findings suggest that impaired mitochondrial function may play a key role in the development of insulin resistance. Mitochondria stay in contact with the endoplasmic reticulum (ER), Golgi membranes and mitochondria-associated membranes (MAM) that are the main places of sphingolipid synthesis. Moreover, mitochondria are capable of synthesizing ceramide though ceramide synthase (CerS) activity. Recently, ceramides have been demonstrated to negatively affect mitochondrial respiratory chain function and fission/fusion activity, which is also a hallmark of T2D. Despite a significant correlation between sphingolipids, mitochondrial dysfunction, insulin resistance and T2D, this subject has not received much attention compared to the direct effect of sphingolipids on the insulin signaling pathway. In this review, we focus on the current state of scientific knowledge regarding the involvement of sphingolipids in the induction of insulin resistance by inhibiting mitochondrial function.

Project description:Accumulation of diacylglycerol (DAG) and sphingolipids is thought to promote skeletal muscle insulin resistance by altering cellular signaling specific to their location. However,the subcellular localization of bioactive lipids in human skeletal muscle is largely unknown. We evaluated subcellular localization of skeletal muscle DAGs and sphingolipids in lean individuals (n = 15), endurance-trained athletes (n = 16), and obese men and women with (n = 12) and without type 2 diabetes (n = 15). Muscle biopsies were fractionated into sarcolemmal, cytosolic, mitochondrial/ER, and nuclear compartments. Lipids were measured using liquid chromatography tandem mass spectrometry, and insulin sensitivity was measured using hyperinsulinemic-euglycemic clamp. Sarcolemmal 1,2-DAGs were not significantly related to insulin sensitivity. Sarcolemmal ceramides were inversely related to insulin sensitivity, with a significant relationship found for the C18:0 species. Sarcolemmal sphingomyelins were also inversely related to insulin sensitivity, with the strongest relationships found for the C18:1, C18:0, and C18:2 species. In the mitochondrial/ER and nuclear fractions, 1,2-DAGs were positively related to, while ceramides were inversely related to, insulin sensitivity. Cytosolic lipids as well as 1,3-DAG, dihydroceramides, and glucosylceramides in any compartment were not related to insulin sensitivity. All sphingolipids but only specific DAGs administered to isolated mitochondria decreased mitochondrial state 3 respiration. These data reveal previously unknown differences in subcellular localization of skeletal muscle DAGs and sphingolipids that relate to whole-body insulin sensitivity and mitochondrial function in humans. These data suggest that whole-cell concentrations of lipids obscure meaningful differences in compartmentalization and suggest that subcellular localization of lipids should be considered when developing therapeutic interventions to treat insulin resistance. National Institutes of Health General Clinical Research Center (RR-00036), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK089170), NIDDK (T32 DK07658), and Colorado Nutrition Obesity Research Center (P30DK048520).

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Dataset Information

Sphingolipids and Mitochondrial Dynamic.

Publications

Sphingolipids and Mitochondrial Dynamic.

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