Lysosomes and mitochondria are both crucial cellular organelles for metabolic homeostasis and organism health. However, mechanisms linking their metabolic activities to promote organism longevity ...remain poorly understood. We discovered that the induction of specific lysosomal signaling mediated by a LIPL-4 lysosomal acid lipase and its lipid chaperone LBP-8 increases mitochondrial ß-oxidation to reduce lipid storage and promote longevity in Caenorhabditis elegans. We further discovered that increased mitochondrial ß-oxidation reduces mitochondrial electron transport chain complex II activity, contributing to the induction of reactive oxygen species in mitochondria (mtROS) and the longevity effect conferred by LIPL-4–LBP-8 signaling. Moreover, by activating the JUN-1 transcription factor downstream of mtROS, the LIPL-4–LBP-8 signaling pathway induces antioxidant targets and oxidative stress tolerance. Together, these results reveal regulatory mechanisms by which lysosomal signaling triggers adjustments in mitochondrial activity and suggest the significance of these metabolic adjustments for improving metabolic fitness, redox homeostasis, and longevity.
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•Lysosomal lipid messenger signaling actively regulates mitochondrial ß-oxidation•Mitochondrial ß-oxidation modulates electron transport chain complex II activity•Lysosomal and mitochondrial pro-longevity signaling converge on JUN-1•Organelle coordination improves metabolic balance, redox homeostasis, and longevity
Ramachandran et al. uncover in C. elegans metabolic and signaling inter-organelle communication between lysosomes, mitochondria, and the nucleus. They demonstrate a crucial role for lysosomal lipid messenger signaling to actively trigger adjustments in mitochondrial activity that in turn coordinate lipid metabolism, redox homeostasis, and longevity.
Modern optical microscopy has granted biomedical scientists unprecedented access to the inner workings of a cell, and revolutionized our understanding of the molecular mechanisms underlying ...physiological and disease states. In spite of these advances, however, visualization of certain classes of molecules (e.g. lipids) at the sub-cellular level has remained elusive. Recently developed chemical imaging modalities – Coherent Anti-Stokes Raman Scattering (CARS) microscopy and Stimulated Raman Scattering (SRS) microscopy – have helped bridge this gap. By selectively imaging the vibration of a specific chemical group, these non-invasive techniques allow high-resolution imaging of individual molecules in vivo, and circumvent the need for potentially perturbative extrinsic labels. These tools have already been applied to the study of fat metabolism, helping uncover novel regulators of lipid storage. Here we review the underlying principle of CARS and SRS microscopy, and discuss the advantages and caveats of each technique. We also review recent applications of these tools in the study of lipids as well as other biomolecules, and conclude with a brief guide for interested researchers to build and use CARS/SRS systems for their own research. This article is part of a Special Issue entitled Tools to study lipid functions.
•Providing an overview of CARS and SRS microscopy•Introducing the principles of Raman Scattering, CARS and SRS microscopy•Overviewing the applications of CARS and SRS microscopy in lipid research and beyond•Highlighting recent advances in SRS and CARS microscopy•A brief guideline for the instrumental setup of SRS and CARS microscopy
Genome-wide association studies (GWAS) identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while ...a large number of single nucleotide polymorphisms associated with type 2 diabetes (T2D) and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed Drosophila model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits.
Disrupting orthologs of certain T2D candidate genes (HHEX, THADA, PPARG, KCNJ11) led to sucrose-dependent toxicity. Tissue-specific knockdown of the HHEX ortholog dHHEX (CG7056) directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of dHHEX led to increased hemolymph glucose and reduced insulin sensitivity.
Candidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple Drosophila approach. To our knowledge, this is the first large-scale effort to study the functional interaction between GWAS-identified candidate genes and an environmental risk factor such as diet in a model organism system.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Advances in modern optical microscopy have provided unparalleled tools to study intracellular structure and function, yet visualizing lipid molecules within a cell remains challenging. Stimulated ...Raman Scattering (SRS) microscopy is a recently developed imaging modality that addresses this challenge. By selectively imaging the vibration of chemical moieties enriched in lipids, this technique allows for rapid imaging of lipid molecules in vivo without the need for perturbative extrinsic labels. SRS microscopy has been effectively employed in the study of fat metabolism, helping uncover novel regulators of lipid storage. This unit provides a brief introduction to the principle of SRS microscopy, and describes methods for its use in imaging lipids in cells, tissues, and whole organisms.
Mitochondrial presequence proteases perform fundamental functions as they process about 70 % of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The ...mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease.
Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human.
Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients' missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria.
Our findings reveal for the first time the role of the mitochondrial intermediate peptidase in human disease. Loss of MIP function results in a syndrome which consists of LVNC, DD, seizures, hypotonia, and cataracts. Our approach highlights the power of data exchange and the importance of an interrelationship between clinical and research efforts for disease gene discovery.
Lysosomes and mitochondria are both crucial cellular organelles for metabolic homeostasis and organism health. However, mechanisms linking their metabolic activities to promote organism longevity ...remain poorly understood. We discovered that the induction of specific lysosomal signaling mediated by a LIPL-4 lysosomal acid lipase and its lipid chaperone LBP-8 increases mitochondrial ß-oxidation to reduce lipid storage and promote longevity in
Caenorhabditis elegans
. We further discovered that increased mitochondrial ß-oxidation reduces mitochondrial electron transport chain complex II activity, contributing to the induction of reactive oxygen species in mitochondria (mtROS) and the longevity effect conferred by LIPL-4–LBP-8 signaling. Moreover, by activating the JUN-1 transcription factor downstream of mtROS, the LIPL-4–LBP-8 signaling pathway induces antioxidant targets and oxidative stress tolerance. Together, these results reveal regulatory mechanisms by which lysosomal signaling triggers adjustments in mitochondrial activity, and suggest the significance of these metabolic adjustments for improving metabolic fitness, redox homeostasis, and longevity.
Ramachandran et al. uncover in
C. elegans
metabolic and signaling inter-organelle communication between lysosomes, mitochondria, and the nucleus. They demonstrate a crucial role for lysosomal lipid messenger signaling to actively trigger adjustments in mitochondrial activity that in turn coordinate lipid metabolism, redox homeostasis, and longevity.
Large-scale networked environments, such as the Internet, possess the characteristics of centralised data, centralised access and centralised control; this gives the user a powerful mechanism for ...building and integrating large repositories of centralised information from diverse resources set. However, a centralised network system with GSM Networks development for a hospital information systems or a health care information portal is still in its infancy. The shortcomings of the currently available tools have made the use of mobile devices more appealing. In mobile computing, the issues such as low bandwidth, high latency wireless Networks, loss or degradation of wireless connections, and network errors or failures need to be dealt with. Other issues to be addressed include system adaptability, reliability, robustness, extensibility, flexibility, and maintainability. GSM approach has emerged as the most viable approach for development of intelligent software applications for wireless mobile devices in a centralized environment, which gives higher band width of 900 MHz for transmission. The e-healthcare system that we have developed provides support for physicians, nurses, pharmacists and other healthcare professionals, as well as for patients and medical devices used to monitor patients. In this paper, we present the architecture and the demonstration prototype.
Quick advancement of the pervasive computing era with its underlying sources of contextual data, services and applications persistently attempts to support a variety of independent devices, with ...different environment, requirements and capabilities. Pervasive computing equipped with many independent collaborating electronic devices like sensors, actuators and complex device capable of sensing, actuating, computing and communicates. These devices belong to different administrative domains and users. As the number of interacting devices grows, there is a need of devices to group with common interest of users. Existing research on grouping approaches dealings with domain specific application, resulting of inflexible and incompatible. In this paper, we propose Device Categorization and capable of dynamic grouping of devices based on a user request. A grouping may contain any number of devices based on the application and its functions need.
Large-scale networked environments, such as the Internet, possess the characteristics of centralised data, centralised access and centralised control; this gives the user a powerful mechanism for ...building and integrating large repositories of centralised information from diverse resources set. However, a centralised network system with GSM Networks development for a hospital information systems or a health care information portal is still in its infancy. The shortcomings of the currently available tools have made the use of mobile devices more appealing. In mobile computing, the issues such as low bandwidth, high latency wireless Networks, loss or degradation of wireless connections, and network errors or failures need to be dealt with. Other issues to be addressed include system adaptability, reliability, robustness, extensibility, flexibility, and maintainability. GSM approach has emerged as the most viable approach for development of intelligent software applications for wireless mobile devices in a centralized environment, which gives higher band width of 900 MHz for transmission. The e-healthcare system that we have developed provides support for physicians, nurses, pharmacists and other healthcare professionals, as well as for patients and medical devices used to monitor patients. In this paper, we present the architecture and the demonstration prototype.
There has been no reported national survey of diabetes in India in the last three decades, although several regional studies show a rising prevalence of diabetes. The aim of this study was to assess ...the prevalence of diabetes and impaired glucose tolerance in six major cities, covering all the regions of the country.
Using a stratified random sampling method, 11216 subjects (5288 men; 5928 women) aged 20 years or above, representative of all socio-economic strata, were tested by OGTT. Demographic, anthropometric, educational and social details were recorded using a standard proforma. Physical activity was categorised using a scoring system. Body mass index (BMI) and waist-to-hip ratio (WHR) were calculated. Glucose tolerance was classified using the 2-h values (WHO criteria). Prevalence estimations were made taking into account the stratified sampling procedure. Group comparisons were done by t-test or analysis of variance or Z-test as relevant. Univariate and multiple logistic regression analyses were used to study the association of variables with diabetes and impaired glucose tolerance.
Age standardised prevalences of diabetes and impaired glucose tolerance were 12.1% and 14.0% respectively, with no gender difference. Diabetes and impaired glucose tolerance showed increasing trend with age. Subjects under 40 years of age had a higher prevalence of impaired glucose tolerance than diabetes (12.8% vs 4.6%, p < 0.0001). Diabetes showed a positive and independent association with age, BMI, WHR, family history of diabetes, monthly income and sedentary physical activity. Age, BMI and family history of diabetes showed associations with impaired glucose tolerance.
This national study shows that the prevalence of diabetes is high in urban India. There is a large pool of subjects with impaired glucose tolerance at a high risk of conversion to diabetes.
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