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Diminished mitochondrial function underlies many rare inborn errors of energy metabolism and contributes to more common age-associated metabolic and neurodegenerative disorders. Thus, boosting mitochondrial biogenesis has been proposed as a potential therapeutic approach for these diseases; however, currently we have a limited arsenal of compounds that can stimulate mitochondrial function. In this study, we designed molybdenum disulfide (MoS 2 ) nanoflowers with predefined atomic vacancies that are fabricated by self-assembly of individual two-dimensional MoS 2 nanosheets. Treatment of mammalian cells with MoS 2 nanoflowers increased mitochondrial biogenesis by induction of PGC-1α and TFAM, which resulted in increased mitochondrial DNA copy number, enhanced expression of nuclear and mitochondrial-DNA encoded genes, and increased levels of mitochondrial respiratory chain proteins. Consistent with increased mitochondrial biogenesis, treatment with MoS 2 nanoflowers enhanced mitochondrial respiratory capacity and adenosine triphosphate production in multiple mammalian cell types. Taken together, this study reveals that predefined atomic vacancies in MoS 2 nanoflowers stimulate mitochondrial function by upregulating the expression of genes required for mitochondrial biogenesis. Mitochondrial dysfunction is linked to various rare genetic disorders and common age-related diseases, but few compounds can stimulate mitochondrial activity. Here, the authors address this issue by developing atomic vacancy-rich molybdenum disulfide nanoparticles that can catalyze intracellular reactive oxygen species to enhance mitochondrial biogenesis and cellular respiration.

Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identified a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that resulted in atrophy of the spleen and thymus and caused a peripheral white blood cell deficiency. We demonstrated that the leukopenia was caused by α-fetoprotein, which required copper and the cell surface receptor CCR5 to promote white blood cell death. We further showed that α-fetoprotein expression was upregulated in several cell types upon inhibition of oxidative phosphorylation. Collectively, our data argue that α-fetoprotein may be secreted by bioenergetically stressed tissue to suppress the immune system, an effect that may explain the recurrent or chronic infections that are observed in a subset of mitochondrial diseases or in other disorders with secondary mitochondrial dysfunction.

Calcium uptake by the mitochondrial calcium uniporter coordinates cytosolic signaling events with mitochondrial bioenergetics. During the past decade all protein components of the mitochondrial calcium uniporter have been identified, including MCU, the pore-forming subunit. However, the specific lipid requirements, if any, for the function and formation of this channel complex are currently not known. Here we utilize yeast, which lacks the mitochondrial calcium uniporter, as a model system to address this problem. We use heterologous expression to functionally reconstitute human uniporter machinery both in wild-type yeast as well as in mutants defective in the biosynthesis of phosphatidylethanolamine, phosphatidylcholine, or cardiolipin (CL). We uncover a specific requirement of CL for in vivo reconstituted MCU stability and activity. The CL requirement of MCU is evolutionarily conserved with loss of CL triggering rapid turnover of MCU homologs and impaired calcium transport. Furthermore, we observe reduced abundance and activity of endogenous MCU in mammalian cellular models of Barth syndrome, which is characterized by a partial loss of CL. MCU abundance is also decreased in the cardiac tissue of Barth syndrome patients. Our work raises the hypothesis that impaired mitochondrial calcium transport contributes to the pathogenesis of Barth syndrome, and more generally, showcases the utility of yeast phospholipid mutants in dissecting the phospholipid requirements of ion channel complexes.

Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into circulation. As a DAMP, mtDNA not only contributes to anti-viral resistance, but also causes pathogenic inflammation in many disease contexts. Cells experiencing mtDNA stress caused by depletion of the mtDNA-packaging protein, transcription factor A, mitochondrial (TFAM) or during herpes simplex virus-1 infection exhibit elongated mitochondria, enlargement of nucleoids (mtDNA–protein complexes) and activation of cGAS–STING innate immune signalling via mtDNA released into the cytoplasm. However, the relationship among aberrant mitochondria and nucleoid dynamics, mtDNA release and cGAS–STING activation remains unclear. Here we show that, under a variety of mtDNA replication stress conditions and during herpes simplex virus-1 infection, enlarged nucleoids that remain bound to TFAM exit mitochondria. Enlarged nucleoids arise from mtDNA experiencing replication stress, which causes nucleoid clustering via a block in mitochondrial fission at a stage when endoplasmic reticulum actin polymerization would normally commence, defining a fission checkpoint that ensures mtDNA has completed replication and is competent for segregation into daughter mitochondria. Chronic engagement of this checkpoint results in enlarged nucleoids trafficking into early and then late endosomes for disposal. Endosomal rupture during transit through this endosomal pathway ultimately causes mtDNA-mediated cGAS–STING activation. Thus, we propose that replication-incompetent nucleoids are selectively eliminated by an adaptive mitochondria–endosomal quality control pathway that is prone to innate immune system activation, which might represent a therapeutic target to prevent mtDNA-mediated inflammation during viral infection and other pathogenic states. Newman et al. show that, upon mitochondrial DNA (mtDNA) replication stress, enlarged nucleoids are trafficked to endosomes. Endosomal rupture releases mtDNA into the cytoplasm, triggering cGAS–STING activation and innate immune signalling.

Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identified a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that resulted in atrophy of the spleen and thymus and caused a peripheral white blood cell deficiency. We demonstrated that the leukopenia was caused by a-fetoprotein, which required copper and the cell surface receptor CCR5 to promote white blood cell death. We further showed that a-fetoprotein expression was upregulated in several cell types upon inhibition of oxidative phosphorylation. Collectively, our data argue that a-fetoprotein may be secreted by bioenergetically stressed tissue to suppress the immune system, an effect that may explain the recurrent or chronic infections that are observed in a subset of mitochondrial diseases or in other disorders with secondary mitochondrial dysfunction.

Power Quality is defined as the ability of electrical grid to supply a clean and stable power supply. Steady-state disturbances such as harmonics, faults, voltage sags and swells, etc., deteriorate the power quality of the grid. To ensure constant voltage and frequency to consumers, power quality should be improved and maintained at a desired level. Although several methods are available to improve the power quality in traditional power grids, significant challenges exist in modern power grids, such as non-linearity, time delay and cyber-attacks issues, which need to be considered and solved. This dissertation proposes novel control methods to address the mentioned challenges and thus to improve the power quality of modern hybrid grids. In hybrid grids, the first issue is faults occurring at different points in the system. To overcome this issue, this dissertation proposes non-linear controlled methods like the Fuzzy Logic controlled Thyristor Switched Capacitor (TSC), Adaptive Neuro Fuzzy Inference System (ANFIS) controlled TSC, and Static Non-Linear controlled TSC. The next issue is the time delay introduced in the network due to its complexities and various computations required. This dissertation proposes two new methods such as the Fuzzy Logic Controller and Modified Predictor to minimize adverse effects of time delays on the power quality enhancement. The last and major issue is the cyber-security aspect of the hybrid grid. This research analyzes the effects of cyber-attacks on various components such as the Energy Storage System (ESS), the automatic voltage regulator (AVR) of the synchronous generator, the grid side converter (GSC) of the wind generator, and the voltage source converter (VSC) of Photovoltaic (PV) system, located in a hybrid power grid. Also, this dissertation proposes two new techniques such as a Non-Linear (NL) controller and a Proportional-Integral (PI) controller for mitigating the adverse effects of cyber-attacks on the mentioned devices, and a new detection and mitigation technique based on the voltage threshold for the Supercapacitor Energy System (SES). Simulation results obtained through the MATLAB/Simulink software show the effectiveness of the proposed new control methods for power quality improvement. Also, the proposed methods perform better than conventional methods.

Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identify a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that results in atrophy of the spleen and thymus and causes a peripheral white blood cell deficiency. We demonstrate that the leukopenia is caused by α-fetoprotein, which requires copper and the cell surface receptor CCR5 to promote white blood cell death. We further show that α-fetoprotein expression is upregulated in several cell types upon inhibition of oxidative phosphorylation, including a muscle cell model of Barth syndrome. Collectively, our data argue that α-fetoprotein secreted by bioenergetically stressed tissue suppresses the immune system, an effect which may explain the recurrent infections that are observed in a subset of mitochondrial diseases or in other disorders with mitochondrial involvement. Competing Interest Statement The authors have declared no competing interest.

While access and adoption issues related to online health management tools (OHMT) have been studied in healthcare contexts, questions remain about whether and how their use impacts patients’ perceptions of healthcare. Drawing on technology affordance and media synchronicity frameworks, we explore how the existence of multiple chronic conditions (MCC) and differences in usage patterns due to a patient’s generation impact these relationships. Utilizing HINTS data, this study provides empirical support for a positive relationship between the utilization of electronic personal health records (e-PHRs) and healthcare quality perceptions, albeit with a caveat that patients with greater healthcare needs as well as millennial and younger generations do not seem to enjoy the same benefits from increased use of e-PHRs. Furthermore, asynchronous patient-provider electronic communication is yet to achieve positive perceptions of better healthcare quality for most users. This research bears implications for the personalization and customization of OHMT to account for variations in patient’s healthcare needs and usage patterns.