Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity

Sphingolipids function as membrane constituents and signaling molecules, with crucial roles in human diseases, from neurodevelopmental disorders to cancer, best exemplified in the inborn errors of sphingolipid metabolism in lysosomes. The dihydroceramide desaturase Delta 4-dihydroceramide desaturase 1 (DEGS1) acts in the last step of a sector of the sphingolipid pathway, de novo ceramide biosynthesis. Defects in DEGS1 cause the recently described hypomyelinating leukodystrophy-18 (HLD18) (OMIM #618404). Here, we reveal that DEGS1 is a mitochondria-associated endoplasmic reticulum membrane-resident (MAM-resident) enzyme, refining previous reports locating DEGS1 at the endoplasmic reticulum only. Using patient fibroblasts, multiomics, and enzymatic assays, we show that DEGS1 deficiency disrupts the main core functions of the MAM: (a) mitochondrial dynamics, with a hyperfused mitochondrial network associated with decreased activation of dynamin-related protein 1; (b) cholesterol metabolism, with impaired sterol O-acyltransferase activity and decreased cholesteryl esters; (c) phospholipid metabolism, with increased phosphatidic acid and phosphatidylserine and decreased phosphatidylethanolamine; and (d) biogenesis of lipid droplets, with increased size and numbers. Moreover, we detected increased mitochondrial superoxide species production in fibroblasts and mitochondrial respiration impairment in patient muscle biopsy tissues. Our findings shed light on the pathophysiology of HLD18 and broaden our understanding of the role of sphingolipid metabolism in MAM function

Altered Expression of miR-181a-5p and miR-23a-3p Is Associated With Obesity and TNFα-Induced Insulin Resistance.

The proinflammatory cytokine TNFα is a key player in insulin resistance (IR). The role of miRNAs in inflammation associated with IR is poorly understood. To investigate miR-181a-5p and miR-23a-3p expression profiles in obesity and to study their role in TNFα-induced IR in adipocytes. Two separate cohorts were used. Cohort 1 was used in adipose tissue (AT) expression studies and included 28 subjects with body mass index (BMI) Expression of miR-181a-5p and miR-23a-3p was reduced in adipose tissue from obese and diabetic subjects and was inversely correlated to adiposity and homeostasis model assessment of IR index. Overexpression of miR-181a-5p and miR-23a-3p in adipocytes upregulated insulin-stimulated AKT activation and reduced TNFα-induced IR, regulating PTEN and S6K expression. Serum levels of miR-181a-5p were reduced in case vs control subjects at baseline, suggesting a prognostic value. Variable importance in projection scores revealed miR-181a-5p had more effect on the model than insulin or glucose at 120 minutes. miR-181a-5p and miR-23a-3p may prevent TNFα-induced IR in adipocytes through modulation of PTEN and S6K expression

The Biological basis of the aging process

El procés biològic bàsic subjacent de l'envelliment va ésser avançat per la teoria de l'envelliment basada en els radicals lliures l'any 1954: la reacció dels radicals lliures actius, produïts fisiològicament en l'organisme, amb els constituents cel·lulars inicia els canvis associats a l'envelliment. La implicació dels radicals lliures en l'envelliment està relacionada amb el seu paper clau en l'origen i l'evolució de la vida. La informació disponible avui en dia ens mostra que la composició específica de les macromolècules cel·lulars (proteïnes, àcids nucleics, lípids i carbohidrats) en les espècies animals longeves tenen intrínsicament una resistència elevada a la modificació oxidativa, la qual cosa probablement contribueix a la longevitat superior d'aquestes espècies. Les espècies longeves també mostren unes taxes reduïdes de producció de radicals lliures i de lesió oxidativa. D'altra banda, la restricció dietària disminueix la producció de radicals lliures i la lesió molecular oxidativa. Aquests canvis estan directament associats a la reducció de la ingesta de proteïnes dels animals sotmesos a restricció, que alhora sembla que són deguts específicament a la reducció de la ingesta de metionina. En aquesta revisió s'emfatitza que una taxa baixa de generació de lesió endògena i una resistència intrínsecament elevada a la modificació de les macromolècules cel·lulars són trets clau de la longevitat de les espècies animals.The basic chemical process underlying aging was first put forward by the free radical theory of aging in 1956; the reaction of active free radicals (normally produced within an organism itself) with cellular constituents initiates the changes associated with aging. The involvement of free radicals in aging is related to their key role in the origin and evolution of life. The specific composition of tissue macromolecules (proteins, nucleic acids, lipids and carbohydrates) in long-lived animal species gives them an intrinsically high resistance to modification that probably contributes to the superior longevity of these species. Long-lived species also show low rates of reactive oxygen species (ROS) generation and oxidative damage to their mitochondria. Dietary restriction further decreases mitochondrial ROS production and oxidative molecular damage due to the decreased intake of dietary proteins. These effects of protein restriction seem to be specifically due to the lowered methionine intake of protein and dietary restricted animals. Both a low rate of generation of endogenous damage and an intrinsically high resistance to the modification of tissue macromolecules are key traits of animal longevity

Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity

Altres ajuts: "Severo Ochoa" program for Centres of Excellence in R&D (CEX2019-000910-S [MCIN/AEI])Sphingolipids function as membrane constituents and signaling molecules, with crucial roles in human diseases, from neurodevelopmental disorders to cancer, best exemplified in the inborn errors of sphingolipid metabolism in lysosomes. The dihydroceramide desaturase Δ4-dihydroceramide desaturase 1 (DEGS1) acts in the last step of a sector of the sphingolipid pathway, de novo ceramide biosynthesis. Defects in DEGS1 cause the recently described hypomyelinating leukodystrophy-18 (HLD18) (OMIM #618404). Here, we reveal that DEGS1 is a mitochondria-associated endoplasmic reticulum membrane-resident (MAM-resident) enzyme, refining previous reports locating DEGS1 at the endoplasmic reticulum only. Using patient fibroblasts, multiomics, and enzymatic assays, we show that DEGS1 deficiency disrupts the main core functions of the MAM: (a) mitochondrial dynamics, with a hyperfused mitochondrial network associated with decreased activation of dynamin-related protein 1; (b) cholesterol metabolism, with impaired sterol O-acyltransferase activity and decreased cholesteryl esters; (c) phospholipid metabolism, with increased phosphatidic acid and phosphatidylserine and decreased phosphatidylethanolamine; and (d) biogenesis of lipid droplets, with increased size and numbers. Moreover, we detected increased mitochondrial superoxide species production in fibroblasts and mitochondrial respiration impairment in patient muscle biopsy tissues. Our findings shed light on the pathophysiology of HLD18 and broaden our understanding of the role of sphingolipid metabolism in MAM function

Loss of SIRT2 leads to axonal degeneration and locomotor disability associated with redox and energy imbalance

Sirtuin 2 (SIRT2) is a member of a family of NAD+ -dependent histone deacetylases (HDAC) that play diverse roles in cellular metabolism and especially for aging process. SIRT2 is located in the nucleus, cytoplasm, and mitochondria, is highly expressed in the central nervous system (CNS), and has been reported to regulate a variety of processes including oxidative stress, genome integrity, and myelination. However, little is known about the role of SIRT2 in the nervous system specifically during aging. Here, we show that middle-aged, 13-month-old mice lacking SIRT2 exhibit locomotor dysfunction due to axonal degeneration, which was not present in young SIRT2 mice. In addition, these Sirt2-/- mice exhibit mitochondrial depletion resulting in energy failure, and redox dyshomeostasis. Our results provide a novel link between SIRT2 and physiological aging impacting the axonal compartment of the central nervous system, while supporting a major role for SIRT2 in orchestrating its metabolic regulation. This underscores the value of SIRT2 as a therapeutic target in the most prevalent neurodegenerative diseases that undergo with axonal degeneration associated with redox and energetic dyshomeostasis.This study was supported by grants from the Spanish Institute for Health Carlos III and 'Fondo Europeo de Desarrollo Regional (FEDER), Union Europea, una manera de hacer Europa' [FIS PI11/01043, FIS PI14/00410], the Autonomous Government of Catalonia [SGR 2014SGR1430] to A.P., The Spanish Institute for Health Carlos III and 'Fondo Europeo de Desarrollo Regional (FEDER), Union Europea, una manera de hacer Europa' [Miguel Servet program CP11/00080, CPII16/00016, FIS PI15/00857] to S.F. and the Center for Biomedical Research on Rare Diseases (CIBERER) to M.R., and the Spanish Institute for Health Carlos III and FEDER funds from European Union ('A way to build Europe') [FIS grants PI14/01115, PI13/00584, and PI14/00328], Foundation La Marató de TV3 [345/C/2014], and the Autonomous Government of Catalonia [2014SGR168] to M.J., M.P.O., and R.P. The studies conducted at the Chromatin Biology Laboratory were supported by the Spanish Ministry of Economy and Competitiveness‐MINECO [SAF2011‐25860, SAF2014‐55964R] to A.V