Adenosine monophosphate-activated protein kinase (AMPK) is a conserved sensor of intracellular energy activated in response to low nutrient availability and environmental stress. In a screen for ...conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic analysis of AMPK or ULK1 in mammalian liver and Caenorhabditis elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 resulted in aberrant accumulation of the autophagy adaptor p62 and defective mitophagy. Reconstitution of ULK1-deficient cells with a mutant ULK1 that cannot be phosphorylated by AMPK revealed that such phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. These findings uncover a conserved biochemical mechanism coupling nutrient status with autophagy and cell survival.
Somatic mitochondrial DNA (mtDNA) mutations contribute to the pathogenesis of age-related disorders, including myelodysplastic syndromes (MDS). The accumulation of mitochondria harboring mtDNA ...mutations in patients with these disorders suggests a failure of normal mitochondrial quality-control systems. The mtDNA-mutator mice acquire somatic mtDNA mutations via a targeted defect in the proofreading function of the mtDNA polymerase, PolgA, and develop macrocytic anemia similar to that of patients with MDS. We observed an unexpected defect in clearance of dysfunctional mitochondria at specific stages during erythroid maturation in hematopoietic cells from aged mtDNA-mutator mice. Mechanistically, aberrant activation of mechanistic target of rapamycin signaling and phosphorylation of uncoordinated 51-like kinase (ULK) 1 in mtDNA-mutator mice resulted in proteasome-mediated degradation of ULK1 and inhibition of autophagy in erythroid cells. To directly evaluate the consequence of inhibiting autophagy on mitochondrial function in erythroid cells harboring mtDNA mutations in vivo, we deleted Atg7 from erythroid progenitors of wild-type and mtDNA-mutator mice. Genetic disruption of autophagy did not cause anemia in wild-type mice but accelerated the decline in mitochondrial respiration and development of macrocytic anemia in mtDNA-mutator mice. These findings highlight a pathological feedback loop that explains how dysfunctional mitochondria can escape autophagy-mediated degradation and propagate in cells predisposed to somatic mtDNA mutations, leading to disease.
•Mitochondrial dysfunction in aged mtDNA-mutator mice is associated with activation of mechanistic target of rapamycin and suppression of autophagy in erythroid cells.•Autophagy maintains mitochondrial function in erythroid progenitors of mtDNA-mutator mice, and disrupting it accelerates onset of anemia.
The ubiquitous m- and μ-calpains are thought to be localized in the cytosolic compartment, as is their endogenous inhibitor calpastatin. Previously, μ-calpain was found to be enriched in ...mitochondrial fractions isolated from rat cerebral cortex and SH-SY5Y neuroblastoma cells, but the submitochondrial localization of μ-calpain was not determined. In the present study, submitochondrial fractionation and digitonin permeabilization studies indicated that both calpain 1 and calpain small subunit 1, which together form μ-calpain, are present in the mitochondrial intermembrane space. The N terminus of calpain 1 contains an amphipathic α-helical domain, and is distinct from the N terminus of calpain 2. Calpain 1, but not calpain 2, was imported into mitochondria. Removal of the N-terminal 22 amino acids of calpain 1 blocked the mitochondrial calpain import, while addition of this N-terminal region to calpain 2 or green fluorescent protein enabled mitochondrial import. The N terminus of calpain 1 was not processed following mitochondrial import, but was removed by autolysis following calpain activation. Calpain small subunit 1 was not directly imported into mitochondria, but was imported in the presence of calpain 1. The presence of a mitochondrial targeting sequence in the N-terminal region of calpain 1 is consistent with the localization of μ-calpain to the mitochondrial intermembrane space and provides new insight into the possible functions of this cysteine protease.
Hematopoietic stem cells (HSCs) are inherently quiescent and self-renewing, yet can differentiate and commit to multiple blood cell types. Intracellular mitochondrial content is dynamic, and there is ...an increase in mitochondrial content during differentiation and lineage commitment in HSCs. HSCs reside in a hypoxic niche within the bone marrow and rely heavily on glycolysis, while differentiated and committed progenitors rely on oxidative phosphorylation. Increased oxidative phosphorylation during differentiation and commitment is not only due to increased mitochondrial content but also due to changes in mitochondrial cytosolic distribution and efficiency. These changes in the intracellular mitochondrial landscape contribute signals toward regulating differentiation and commitment. Thus, a functional relationship exists between the mitochondria in HSCs and the state of the HSCs (i.e., stemness vs. differentiated). This review focuses on how autophagy-mediated mitochondrial clearance (i.e., mitophagy) may affect HSC mitochondrial content, thereby influencing the fate of HSCs and maintenance of hematopoietic homeostasis.
Calpains and caspases are cysteine endopeptidases which share many similar substrates. Caspases are essential for caspase-dependent apoptotic death where calpains may play an augmentive role, while ...calpains are strongly implicated in necrotic cell death morphologies. Previous studies have demonstrated a down-regulation in the expression of many components of the caspase-dependent cell death pathway during CNS development. We therefore sought to determine if there is a corresponding upregulation of calpains. The major CNS calpains are the μ-and m-isoforms, composed of the unique 80 kDa calpain 1 and 2 subunits, respectively, and the shared 28 kDa small subunit. In rat brain, relative protein and mRNA levels of calpain 1, calpain 2, caspase 3, and the endogenous calpain inhibitor-calpastatin, were evaluated using western blot and real-time RT-PCR. The developmental time points examined ranged from embryonic day 18 until postnatal day 90. Calpain 1 and calpastatin protein and mRNA levels were low at early developmental time points and increased dramatically by P30. Conversely, caspase-3 expression was greatest at E18, and was rapidly downregulated by P30. Calpain 2 protein and mRNA levels were relatively constant throughout the E18-P90 age range examined. The inverse relationship of calpain 1 and caspase 3 levels during CNS development is consistent with the shift from caspase-dependent to caspase-independent cell death mechanisms following CNS injury in neonatal vs. adult rat brain.
Accidents and Osteoporosis are two prime reasons of femur bone fractures. Osteoporosis causes weakening of bone in elder patients. Proper treatment during surgery will help patients for early ...rehabilitation. This paper portrays a review of concerned literature identified with Biomedical Image analysis and modelling of femur bone fractures for an operative planning. Paper intended to review literature for Biomedical image preprocessing to identify the proper region of Interest (ROI) by using an appropriate image modality, building up a 3D model of femur bone structure using image database with software, analysis of created 3D model for applying implant and its parametric analysis for evaluation of virtual surgery and operative planning to surgeon depending on assessment report produced utilising earlier advances. Such sort of work will keep away from mismatches of fracture which may prompt genuine implanted complications for patients including secondary fractures, poor anatomical alignment and bone debilitating too. Paper will summarise conclusion of concern literature to guide new researcher to start with
J. Neurochem. (2010) 10.1111/j.1471-4159.2010.06579.x Activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) are implicated in the pathophysiology of spinal cord injury (SCI). ...However, the specific functions of individual ERK isoforms in neurodegeneration are largely unknown. We investigated the hypothesis that ERK2 activation may contribute to pathological and functional deficits following SCI and that ERK2 knockdown using RNA interference may provide a novel therapeutic strategy for SCI. Lentiviral ERK2 shRNA and siRNA were utilized to knockdown ERK2 expression in the spinal cord following SCI. Pre-injury intrathecal administration of ERK2 siRNA significantly reduced excitotoxic injury-induced activation of ERK2 (p < 0.001) and caspase 3 (p < 0.01) in spinal cord. Intraspinal administration of lentiviral ERK2 shRNA significantly reduced ERK2 expression in the spinal cord (p < 0.05), but did not alter ERK1 expression. Administration of the lentiviral ERK2 shRNA vector 1 week prior to severe spinal cord contusion injury resulted in a significant improvement in locomotor function (p < 0.05), total tissue sparing (p < 0.05), white matter sparing (p < 0.05), and gray matter sparing (p < 0.05) 6 weeks following severe contusive SCI. Our results suggest that ERK2 signaling is a novel target associated with the deleterious consequences of spinal injury.
Lithium-sulfur batteries (LSB) have gained enormous attention owing to its high theoretical energy density and capacity. However, poor utilization of sulfur and sluggish reaction kinetics leads to ...unsatisfactory performance of these batteries. Herein, we tune the electrical properties of a carbon cloth derived from waste cotton by suitably selecting the carbonization temperature and utilize it as a current collector in LSB. The fibrous architecture with enhanced electrical conductivity provides efficient channels for electron transport leading to better activation of sulfur. As a result, LSB delivers a high initial discharge capacity of 1171 mA h g−1 at 0.1C rate. Further, LSB cell with addition of a second layer as upper collector between cathode and separator exhibits a high initial capacity of 592 mA h g−1 at an even faster rate of 1C and retains 81.2% of the initial capacity after 500 cycles with a low capacity fade of 0.033% per cycle. Even with a higher loading of 3.05 mg cm−2, the LSB maintains a capacity of 423 mA h g−1 at 0.2C after 200 cycles with 98% Coulombic efficiency. Moreover, the flexible current collector opens possibilities for development of flexible and wearable energy storage devices.
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•Effect of carbonization temperature on cotton derived carbon cloth is examined.•Prepared carbon cloths are used as current collectors in LSB.•Enhanced electrical conductivity of CC1300 resulted in better activation of sulfur.•LSB with upper collector showed good electrochemical performance at fast C-rates.
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•Hollow TiO2@Fe2O3 Nanofiber were prepared by a simple electrospinning technique.•TiO2@Fe2O3 nanofibers were used as functional additive in Lithium sulfur cell.•The Lithium sulfur ...cell with TiO2@Fe2O3 nanofibers demonstrated excellent electrochemical performance.•TiO2@Fe2O3 nanofibers promotes capture conversion of polysulfides.
High theoretical capacity (1675 mA h g−1) and energy density (2600 Wh kg−1) in addition to low cost, non-toxicity and natural abundance stimulates the exploration of sulfur as a potential cathode material. However, serious capacity fade and poor reaction kinetics leads to untimely failure which prevents the practical commodification of these batteries. Here, a simple and versatile electrospinning technique has been employed to prepare a polymeric template to fabricate hollow metal oxide@metal oxide nanofibers. The hollow fibrous shell with large specific surface area is incorporated as an anchoring material comprising of distinct crystalline phases separated by amorphous domains. Meanwhile, the encapsulated metal oxide nanoparticles ensure efficient conversion of soluble polysulfides thereby, promoting the reaction kinetics and avoiding any surface passivation of anchoring material. The LSB cell with 5 % TiO2@Fe2O3 nanofiber additives delivers impressively in the rate capability test with stable capacities of 620 and 480 mA h g−1 at 1C and 2C rate, respectively. Moreover, an excellent cycling performance is attained with a fade rate of 0.092 % per cycle over 500 cycles at 0.5C-rate. The findings of this work shall provide a pathway for facile preparation of functional metal oxide composites for simultaneous trapping and conversion of polysulfide species in sulfur batteries.
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