Las enfermedades raras en las patologías neurometabólicas

Metabolic myopathies are genetic disorders that decrease the capacity of skeletal muscle to use energy substrates and ATP. These disturbances can be classified into three categories: i) disorders of carbohydrate metabolism (glycogen and glucose), ii) defects in lipid metabolism, and iii) dysfunctions of oxidative phosphorylation -OXPHOS-. The first two are caused by enzyme deficiencies involved in the metabolic pathways of degradation and synthesis of carbohydrates and lipids, and although they show distinct clinical manifestations, exercise intolerance is a predominant symptom present in most of them. Although a good number of patients with these muscle disorders display symptoms in childhood, the diagnosis is often delayed until the second and third decades of life. Therefore, recognizing the clinical features of these deficiencies can lead to an earlier diagnosis and better treatment. Mitochondrial diseases are a group of disorders caused by an alteration of the oxidative phosphorylation system, that leads to a deficient synthesis of ATP. This system is composed of proteins codified in the two genetic systems of the cell, the nuclear and mitochondrial genomes, and, therefore, the mode of inheritance could be either Mendelian or maternal. This review will describe the special characteristics of the mitochondrial genetic system and the main mutations in mtDNA that cause human diseases.Las miopatías metabólicas son un grupo de trastornos genéticos que disminuyen la capacidad del músculo esquelético para utilizar sustratos energéticos y sintetizar ATP. Estas alteraciones pueden clasificarse en tres tipos fundamentalmente: i) trastornos del metabolismo de los carbohidratos (del glucógeno y de la glucosa), ii) defectos del metabolismo lipídico, y iii) alteraciones de la fosforilación oxidativa –OXPHOS-. Las dos primeras se deben a deficiencias enzimáticas de las rutas metabólicas de degradación y síntesis de glúcidos y lípidos y muestran diversas manifestaciones clínicas, pero una buena parte de ellas cursan con intolerancia al ejercicio. Aunque un buen número de pacientes con estos trastornos musculares presentan síntomas en la infancia, el diagnóstico normalmente se retrasa hasta la segunda y tercera década de la vida. Por tanto, reconocer las características clínicas de estas deficiencias conduce a un diagnóstico precoz y a un mejor tratamiento. Las enfermedades mitocondriales son un grupo de trastornos originados por una deficiencia en la síntesis de ATP a través del sistema de fosforilación oxidativa. Este sistema está formado por proteínas codificadas en los dos genomas de la célula (nuclear y mitocondrial) y, por tanto, pueden presentar un modelo de herencia mendeliano o materno. En esta revisión se describirán las características especiales del sistema genético mitocondrial y las principales mutaciones que causan enfermedades en humanos

Phenotype consequences of myophosphorylase dysfunction: insights from the McArdle mouse model

McArdle disease, caused by inherited deficiency of the enzyme muscle glycogen phosphorylase (GP-MM), is arguably the paradigm of exercise intolerance. The recent knock-in (p.R50X/p.R50X) mouse disease model allows an investigation of the phenotypic consequences of muscle glycogen unavailability and the physiopathology of exercise intolerance. We analysed, in 2-month-old mice [wild-type (wt/wt), heterozygous (p.R50X/wt) and p.R50X/p.R50X)], maximal endurance exercise capacity and the molecular consequences of an absence of GP-MM in the main glycogen metabolism regulatory enzymes: glycogen synthase, glycogen branching enzyme and glycogen debranching enzyme, as well as glycogen content in slow-twitch (soleus), intermediate (gastrocnemius) and glycolytic/fast-twitch (extensor digitorum longus; EDL) muscles.Fondo de Investigaciones Sanitarias (FIS) PI12/009144.731 JCR (2015) Q1, 46/256 Neurosciences, 7/83 PhysiologyUE

The mitochondrial succinate dehydrogenase complex controls the STAT3-IL-10 pathway in inflammatory macrophages

The functions of macrophages are tightly regulated by their metabolic state. However, the role of the mitochondrial electron transport chain (ETC) in macrophage functions remains understudied. Here, we provide evidence that the succinate dehydrogenase (SDH)/complex II (CII) is required for respiration and plays a role in controlling effector responses in macrophages. We find that the absence of the catalytic subunits Sdha and Sdhb in macrophages impairs their ability to effectively stabilize HIF-1α and produce the pro-inflammatory cytokine IL-1β in response to LPS stimulation. We also arrive at the novel result that both subunits are essential for the LPS-driven production of IL-10, a potent negative feedback regulator of the macrophage inflammatory response. This phenomenon is explained by the fact that the absence of Sdha and Sdhb leads to the inhibition of Stat3 tyrosine phosphorylation, caused partially by the excessive accumulation of mitochondrial reactive oxygen species (mitoROS) in the knockout cells.Funding information: Agencia Estatal de Investigación, Grant Number PID2020-118517RB-I00; Consejería de Educación, Junta de Castilla y León, Grant Number VA172P20; Consejería de Sanidad, Junta de Castilla y León, Grant Number GRS 2201/A/2020; Programa Estratégico Instituto de Biología y Genética Molecular (IBGM), Junta de Castilla y León, Award Number CCVC8485; Switzerland National Science Foundation, Grant Number 310030_200796

The mitochondrial succinate dehydrogenase complex controls the STAT3-IL-10 pathway in inflammatory macrophages

Summary: The functions of macrophages are tightly regulated by their metabolic state. However, the role of the mitochondrial electron transport chain (ETC) in macrophage functions remains understudied. Here, we provide evidence that the succinate dehydrogenase (SDH)/complex II (CII) is required for respiration and plays a role in controlling effector responses in macrophages. We find that the absence of the catalytic subunits Sdha and Sdhb in macrophages impairs their ability to effectively stabilize HIF-1α and produce the pro-inflammatory cytokine IL-1β in response to LPS stimulation. We also arrive at the novel result that both subunits are essential for the LPS-driven production of IL-10, a potent negative feedback regulator of the macrophage inflammatory response. This phenomenon is explained by the fact that the absence of Sdha and Sdhb leads to the inhibition of Stat3 tyrosine phosphorylation, caused partially by the excessive accumulation of mitochondrial reactive oxygen species (mitoROS) in the knockout cells