Institute for Research in Biomedicine (IRB Barcelona), CIBER de Diabetes y Enfermedades Metabólicas Asociadas, and Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de ...Barcelona, Barcelona, Spain
The meaning of the word mitochondrion (from the Greek mitos , meaning thread, and chondros , grain) illustrates that the heterogeneity of mitochondrial morphology has been known since the first descriptions of this organelle. Such a heterogeneous morphology is explained by the dynamic nature of mitochondria. Mitochondrial dynamics is a concept that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial architecture (morphology and distribution), and connectivity mediated by tethering and fusion/fission events. The relevance of these events in mitochondrial and cell physiology has been partially unraveled after the identification of the genes responsible for mitochondrial fusion and fission. Furthermore, during the last decade, it has been identified that mutations in two mitochondrial fusion genes ( MFN2 and OPA1 ) cause prevalent neurodegenerative diseases (Charcot-Marie Tooth type 2A and Kjer disease/autosomal dominant optic atrophy). In addition, other diseases such as type 2 diabetes or vascular proliferative disorders show impaired MFN2 expression. Altogether, these findings have established mitochondrial dynamics as a consolidated area in cellular physiology. Here we review the most significant findings in the field of mitochondrial dynamics in mammalian cells and their implication in human pathologies.
Cellular organelles are not static but show dynamism—a property that is likely relevant for their function. In addition, they interact with other organelles in a highly dynamic manner. In this ...review, we analyze the proteins involved in the interaction between mitochondria and other cellular organelles, especially the endoplasmic reticulum, lipid droplets, and lysosomes. Recent results indicate that, on one hand, metabolic alterations perturb the interaction between mitochondria and other organelles, and, on the other hand, that deficiency in proteins involved in the tethering between mitochondria and the ER or in specific functions of the interaction leads to metabolic alterations in a variety of tissues. The interaction between organelles is an emerging field that will permit to identify key proteins, to delineate novel modulation pathways, and to elucidate their implications in human disease.
This review analyzes dynamic interactions between mitochondria and other organelles, the effects of metabolic alterations on these interactions and the impact of deficient organelle tethering on cellular and organelle metabolism.
Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the ...contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate-SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation.
Parkinson's disease (PD) is associated with the degeneration of ventral midbrain dopaminergic neurons (vmDAns) and the accumulation of toxic α-synuclein. A non-cell-autonomous contribution, in ...particular of astrocytes, during PD pathogenesis has been suggested by observational studies, but remains to be experimentally tested. Here, we generated induced pluripotent stem cell-derived astrocytes and neurons from familial mutant LRRK2 G2019S PD patients and healthy individuals. Upon co-culture on top of PD astrocytes, control vmDAns displayed morphological signs of neurodegeneration and abnormal, astrocyte-derived α-synuclein accumulation. Conversely, control astrocytes partially prevented the appearance of disease-related phenotypes in PD vmDAns. We additionally identified dysfunctional chaperone-mediated autophagy (CMA), impaired macroautophagy, and progressive α-synuclein accumulation in PD astrocytes. Finally, chemical enhancement of CMA protected PD astrocytes and vmDAns via the clearance of α-synuclein accumulation. Our findings unveil a crucial non-cell-autonomous contribution of astrocytes during PD pathogenesis, and open the path to exploring novel therapeutic strategies aimed at blocking the pathogenic cross talk between neurons and glial cells.
Display omitted
•Astrocytes contribute to dopaminergic neurodegeneration in PD•Non-cell-autonomous damage is triggered by impaired autophagy in PD astrocytes•Dysfunctional PD astrocytes accumulate and transfer α-synuclein to healthy DAns•CMA activator drug prevents α-synuclein accumulation and neurodegeneration
In this article, Consiglio and colleagues show that PD iPSC-derived astrocytes contribute to dopaminergic neurodegeneration, indicating an important role for astrocytes in the pathogenesis of Parkinson's disease. PD astrocytes display dysfunctional chaperone-mediated autophagy (CMA), impaired macroautophagy, and progressive α-synuclein accumulation. In co-culture, PD astrocytes transfer α-synuclein to vmDAns and trigger dopaminergic neuronal cell death that can be rescued by treatment with a chemical enhancement of CMA.
Diabetes mellitus—whether driven by insulin deficiency or insulin resistance—causes major alterations in muscle metabolism. These alterations have an impact on nutrient handling, including the ...metabolism of glucose, lipids, and amino acids, and also on muscle mass and strength. However, the ways in which the distinct forms of diabetes affect muscle mass differ greatly. The most common forms of diabetes mellitus are type 1 and type 2. Thus, whereas type 1 diabetic subjects without insulin treatment display a dramatic loss of muscle, most type 2 diabetic subjects show no changes or even an increase in muscle mass. However, the most commonly used rodent models of type 2 diabetes are characterized by muscle atrophy and do not mimic the features of the disease in humans in terms of muscle mass. In this review, we analyze the processes that are differentially regulated under these forms of diabetes and propose regulatory mechanisms to explain them.
Objectives
To describe the status of implants in periodontally compromised patients who regularly receive supportive periodontal therapy (SPT) and to determine the factors associated to peri‐implant ...inflammatory disease in those patients.
Material and methods
Clinical and radiographic data of implants in periodontal patients who, after being treated and included in a SPT programme, wore implant prostheses for at least 6 months were recorded. The implants were classified according to the criteria of the 6th European Workshop on Periodontology in health, mucositis and peri‐implantitis. Logistic regression analysis was performed to analyse the individual and adjusted effects of each study variable on mucositis or peri‐implantitis, using SUDAAN to account for clustering (multiple implants within the patient).
Results
A total of 786 implants were placed in 239 patients. At patient level, 60.3%, 24.7% and 15.1% were classified as healthy, mucositis and peri‐implantitis patients, respectively. At implant level, the respective percentages were 77.4%, 12.8% and 9.8%. For mucositis, at implant level, the adjusted ORs indicate a significant association with plaque index (P = 0.050), type of periodontitis (P = 0.030) and location (P = 0.045). For peri‐implantitis, the adjusted ORs indicate a significant association with plaque index (P < 0.001) and location (P = 0.002).
Conclusions
The prevalence of peri‐implant inflammatory disease in periodontal patients who regularly undergo SPT is clinically significant. The factors associated with peri‐implant inflammatory disease were plaque index and implant location, and mucositis was also affected by the type of periodontitis the patient had.
Mitochondrial fusion and fission events, collectively known as mitochondrial dynamics, act as quality control mechanisms to ensure mitochondrial function and fine‐tune cellular bioenergetics. ...Defective mitofusin 2 (Mfn2) expression and enhanced mitochondrial fission in skeletal muscle are hallmarks of insulin‐resistant states. Interestingly, Mfn2 is highly expressed in brown adipose tissue (BAT), yet its role remains unexplored. Using adipose‐specific Mfn2 knockout (Mfn2‐adKO) mice, we demonstrate that Mfn2, but not Mfn1, deficiency in BAT leads to a profound BAT dysfunction, associated with impaired respiratory capacity and a blunted response to adrenergic stimuli. Importantly, Mfn2 directly interacts with perilipin 1, facilitating the interaction between the mitochondria and the lipid droplet in response to adrenergic stimulation. Surprisingly, Mfn2‐adKO mice were protected from high‐fat diet‐induced insulin resistance and hepatic steatosis. Altogether, these results demonstrate that Mfn2 is a mediator of mitochondria to lipid droplet interactions, influencing lipolytic processes and whole‐body energy homeostasis.
Synopsis
Mitofusin 2 (Mfn2) is critical for brown adipose tissue thermogenic function and participates in the functional relationship between mitochondria and lipid droplets.
Mfn2 ablation disrupts brown adipose tissue thermogenic function.
Mfn2 regulates the docking of mitochondria to lipid droplets in BAT.
Adipose tissue Mfn2 deficiency protects against high‐fat diet‐induced insulin resistance.
Adipose tissue Mfn2 influences inter‐organ communication and hepatic lipid accumulation.
Mitofusin 2 (Mfn2) is critical for brown adipose tissue thermogenic function and participates in the functional relationship between mitochondria and lipid droplets.
Mitochondrial dysfunction and accumulation of damaged mitochondria are considered major contributors to aging. However, the molecular mechanisms responsible for these mitochondrial alterations remain ...unknown. Here, we demonstrate that mitofusin 2 (Mfn2) plays a key role in the control of muscle mitochondrial damage. We show that aging is characterized by a progressive reduction in Mfn2 in mouse skeletal muscle and that skeletal muscle Mfn2 ablation in mice generates a gene signature linked to aging. Furthermore, analysis of muscle Mfn2‐deficient mice revealed that aging‐induced Mfn2 decrease underlies the age‐related alterations in metabolic homeostasis and sarcopenia. Mfn2 deficiency reduced autophagy and impaired mitochondrial quality, which contributed to an exacerbated age‐related mitochondrial dysfunction. Interestingly, aging‐induced Mfn2 deficiency triggers a ROS‐dependent adaptive signaling pathway through induction of HIF1α transcription factor and BNIP3. This pathway compensates for the loss of mitochondrial autophagy and minimizes mitochondrial damage. Our findings reveal that Mfn2 repression in muscle during aging is a determinant for the inhibition of mitophagy and accumulation of damaged mitochondria and triggers the induction of a mitochondrial quality control pathway.
Synopsis
Reduced muscle mitochondrial fusion protein Mfn2 is a determinant for age‐induced decay of mitochondrial function and quality, contributing to age‐associated metabolic alterations and sarcopenia.
Aging is characterized by a reduction of Mfn2 protein expression in skeletal muscle.
Reduction in Mfn2 impairs mitochondrial quality control and mitochondrial function in skeletal muscle.
Mfn2‐deficient mice show unhealthy aging characterized by impaired metabolic homeostasis and sarcopenia.
Reduction in Mfn2 triggers a mitochondrial retrograde signalling pathway in order to minimize mitochondrial damage.
Reduced muscle mitochondrial fusion protein Mfn2 is a determinant for age‐induced decay of mitochondrial function and quality, contributing to age‐associated metabolic alterations and sarcopenia.
Mitochondria are dynamic organelles that frequently undergo fission and fusion processes, and imbalances in these processes may be involved in obesity and insulin resistance.
The present work had the ...following aims: (a) to evaluate whether the mitochondrial dysfunction present in the hepatic steatosis induced by a high-fat diet is associated with changes in mitochondrial dynamics and morphology; (b) to evaluate whether effects on the above parameters differ between high-lard and high-fish-oil diets, as it has been suggested that fish oil may have anti-obesity and anti-steatotic effects by stimulating fatty acids utilisation.
The development of hepatic steatosis and insulin resistance was monitored in rats fed a high-lard or high-fish-oil diet. Immunohistochemical and electronic microscopic observations were performed on liver sections. In isolated liver mitochondria, assessments of fatty acids oxidation rate, proton conductance and oxidative stress (by measuring H2O2 release and aconitase activity) were performed. Western blot and immunohistochemical analyses were performed to evaluate the presence of proteins involved in mitochondrial dynamics (i.e., fusion and fission processes). To investigate the fusion process, mitofusin 2 and autosomal dominant optic atrophy-1 (OPA1) were analysed. To investigate the fission process, the presence of dynamin-related protein 1 (Drp1) and fission 1 protein (Fis1) was assessed.
High-lard feeding elicited greater hepatic lipid accumulation, insulin resistance with associated mitochondrial dysfunction, greater oxidative stress and a shift towards mitochondrial fission processes (versus high-fish-oil feeding, which had an anti-steatotic effect associated with increased mitochondrial fusion processes).
Different types of high-fat diets differ in their effect on mitochondrial function and dynamic behaviour, leading to different cellular adaptations to over-feeding.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mitochondrial dysfunction has been reported in skeletal muscle of obese subjects and of type 2 diabetic patients. Reduced mitochondrial mass and defective activity have been proposed to explain this ...dysfunction. Alterations in mitochondrial function may be crucial to explain the metabolic changes and insulin resistance that characterize both obesity and type 2 diabetes. Consequently, the identification of the primary mechanisms involved is of great relevance.
Mitochondrial dynamics refers to the movement of mitochondria along the cytoskeleton and also to the regulation of mitochondrial morphology and distribution, which depend on fusion and fission events. In recent years, some of the proteins that participate in mitochondrial fusion and fission have been identified in mammalian cells. Recent evidence indicates that proteins participating in these processes are also involved in metabolism. The mitochondrial fusion protein mitofusin 2 stimulates respiration, substrate oxidation and the expression of subunits that participate in respiratory complexes in cultured cells. In this regard, skeletal muscle of obese subjects and of type 2 diabetic patients shows reduced mitofusin 2 expression. Therefore, alterations in the activity of the proteins involved in mitochondrial dynamics, and particularly mitofusin 2, may participate in the reduced mitochondrial function present in skeletal muscle in obesity and in type 2 diabetes.
PDF
