The mitochondrial network is not only required for the production of energy, essential cofactors and amino acids, but also serves as a signaling hub for innate immune and apoptotic pathways. Multiple ...mechanisms have evolved to identify and combat mitochondrial dysfunction to maintain the health of the organism. One such pathway is the mitochondrial unfolded protein response (UPRmt ), which is regulated by the mitochondrial import efficiency of the transcription factor ATFS-1 in C. elegans and potentially orthologous transcription factors in mammals (ATF4, ATF5, CHOP). Upon mitochondrial dysfunction, import of ATFS-1 into mitochondria is reduced, allowing it to be trafficked to the nucleus where it promotes the expression of genes that promote survival and recovery of the mitochondrial network. Here, we discuss recent findings underlying UPRmt signal transduction and how this adaptive transcriptional response may interact with other mitochondrial stress response pathways.
The mitochondrial network is not only required for the production of energy, essential cofactors and amino acids, but also serves as a signaling hub for innate immune and apoptotic pathways. Multiple ...mechanisms have evolved to identify and combat mitochondrial dysfunction to maintain the health of the organism. One such pathway is the mitochondrial unfolded protein response (UPR
), which is regulated by the mitochondrial import efficiency of the transcription factor ATFS-1 in C. elegans and potentially orthologous transcription factors in mammals (ATF4, ATF5, CHOP). Upon mitochondrial dysfunction, import of ATFS-1 into mitochondria is reduced, allowing it to be trafficked to the nucleus where it promotes the expression of genes that promote survival and recovery of the mitochondrial network. Here, we discuss recent findings underlying UPR
signal transduction and how this adaptive transcriptional response may interact with other mitochondrial stress response pathways.
Mitochondrial dysfunction is pervasive in human pathologies such as neurodegeneration, diabetes, cancer, and pathogen infections as well as during normal aging. Cells sense and respond to ...mitochondrial dysfunction by activating a protective transcriptional program known as the mitochondrial unfolded protein response (UPRmt), which includes genes that promote mitochondrial protein homeostasis and the recovery of defective organelles 1, 2. Work in Caenorhabditis elegans has shown that the UPRmt is regulated by the transcription factor ATFS-1, which is regulated by organelle partitioning. Normally, ATFS-1 accumulates within mitochondria, but during respiratory chain dysfunction, high levels of reactive oxygen species (ROS), or mitochondrial protein folding stress, a percentage of ATFS-1 accumulates in the cytosol and traffics to the nucleus where it activates the UPRmt 2. While similar transcriptional responses have been described in mammals 3, 4, how the UPRmt is regulated remains unclear. Here, we describe a mammalian transcription factor, ATF5, which is regulated similarly to ATFS-1 and induces a similar transcriptional response. ATF5 expression can rescue UPRmt signaling in atfs-1-deficient worms requiring the same UPRmt promoter element identified in C. elegans. Furthermore, mammalian cells require ATF5 to maintain mitochondrial activity during mitochondrial stress and promote organelle recovery. Combined, these data suggest that regulation of the UPRmt is conserved from worms to mammals.
•Mammalian ATF5 regulates the mitochondrial UPR in worms lacking ATFS-1•ATF5 induces transcription of mammalian mitochondrial proteostasis genes•ATF5 localizes to mitochondria and nuclei, suggesting regulation similar to ATFS-1•ATF5 promotes mitochondrial function and recovery from mitochondrial stress
Fiorese et al. identify the transcription factor ATF5 as a mediator of a mammalian mitochondrial unfolded protein response. Their investigation suggests that ATF5 communicates mitochondrial status to the nucleus to mediate the induction of a mitochondrial protective program that includes mitochondrial chaperone and protease genes.
The emergence of "big data" initiatives has led to the need for tools that can automatically extract valuable chemical information from large volumes of unstructured data, such as the scientific ...literature. Since chemical information can be present in figures, tables, and textual paragraphs, successful information extraction often depends on the ability to interpret all of these domains simultaneously. We present a complete toolkit for the automated extraction of chemical entities and their associated properties, measurements, and relationships from scientific documents that can be used to populate structured chemical databases. Our system provides an extensible, chemistry-aware, natural language processing pipeline for tokenization, part-of-speech tagging, named entity recognition, and phrase parsing. Within this scope, we report improved performance for chemical named entity recognition through the use of unsupervised word clustering based on a massive corpus of chemistry articles. For phrase parsing and information extraction, we present the novel use of multiple rule-based grammars that are tailored for interpreting specific document domains such as textual paragraphs, captions, and tables. We also describe document-level processing to resolve data interdependencies and show that this is particularly necessary for the autogeneration of chemical databases since captions and tables commonly contain chemical identifiers and references that are defined elsewhere in the text. The performance of the toolkit to correctly extract various types of data was evaluated, affording an F-score of 93.4%, 86.8%, and 91.5% for extracting chemical identifiers, spectroscopic attributes, and chemical property attributes, respectively; set against the CHEMDNER chemical name extraction challenge, ChemDataExtractor yields a competitive F-score of 87.8%. All tools have been released under the MIT license and are available to download from http://www.chemdataextractor.org .
Mitochondria are required for numerous essential metabolic processes including the regulation of apoptosis; therefore, proper maintenance of the mitochondrial proteome is crucial. The protein-folding ...environment in mitochondria is challenged by organelle architecture, the presence of reactive oxygen species and the difficulties associated with assembly of the electron transport chain, which consists of components encoded by both the mitochondrial and the nuclear genomes. Mitochondria have dedicated molecular chaperones and proteases that promote proper protein folding, complex assembly and quality control. Work in cultured mammalian cells and Caenorhabditis elegans has yielded clues to the mechanisms linking perturbations in the protein-folding environment in the mitochondrial matrix to the expression of nuclear genes encoding mitochondrial proteins. Here, we review the current knowledge of this mitochondrial unfolded protein response (UPRmt), compare it with the better understood UPR of the endoplasmic reticulum and highlight its potential impact on development and disease.
The mitochondrial proteome encompasses more than a thousand proteins, which are encoded by the mitochondrial and nuclear genomes. Mitochondrial biogenesis and network health relies on maintenance of ...protein import pathways and the protein-folding environment. Cell-extrinsic or -intrinsic stressors that challenge mitochondrial proteostasis negatively affect organellar function. During conditions of stress, cells use impaired protein import as a sensor for mitochondrial dysfunction to activate a stress response called the mitochondrial unfolded protein response (UPR
). UPR
activation leads to an adaptive transcriptional program that promotes mitochondrial recovery, metabolic adaptations, and innate immunity. In this review, we discuss the regulation of UPR
activation as well as its role in maintaining mitochondrial homeostasis in physiological and pathological scenarios.
Our objective was to assess the five‐year impact of Medicaid expansion on community health centers using nationally representative data on all US health centers, where 35% of the patient population ...was uninsured prior to expansion. We examined the impact of expansion on insurance coverage and type, quality of care, and utilization of services. Understanding longer term effects of expansion is critical given that some quality measures may take multiple years to be clinically affected while pent‐up demand may also result in short‐term effects on utilization.
Using the 2011‐2018 Uniform Data System, we conducted a difference‐in‐differences (DID) analysis with inverse probability of treatment weights (IPTWs), based on propensity scores, to compare outcomes in centers located in expansion versus nonexpansion states. Outcomes included insurance coverage type (none, Medicaid, private), 47 utilization measures (number of patient visits) for select categories of service and chronic conditions based on CPT and ICD codes, and 8 primary care quality measures that may be sensitive to Medicaid expansion. Propensity scores included 23 baseline covariates (patient demographics, health center organizational features, county‐level characteristics). For each measure, using IPTWs, a difference‐in‐difference was calculated using generalized linear models. We included a treatment indicator, time in postperiod indicator, treatment*post‐time interaction, vector of time‐variant covariates, state and year fixed effects, and clustered errors at the center‐level.
100% sample of US health centers (N = 1061 centers/year, or 24.5 million patients/year, after exclusions).
By 2018, compared to centers in nonexpansion states, centers in expansion states experienced a 12.0 percentage‐point decrease in the percent patients without health insurance (
P
< .001) and a 13.2 percentage‐point increase in those with Medicaid coverage (
P
< .001). These gains were largely driven by coverage gains in 2014‐2015.
Medicaid expansion was associated with improved quality of care for 5 of 8 measures, though relative gains in quality dissipated over the five‐year postperiod for some measures (eg, asthma treatment) while relative gains for other measures (eg, colorectal cancer screening, diabetes control) were not detected until several years postexpansion. For instance, by 2018, expansion was a 4.5 percentage‐point relative increase in rates of HbA1c control among diabetics (95% CI 2.2‐6.8) and a 3.5 percentage‐point relative increase in colorectal cancer screening rates (95% CI 0.1‐6.9); neither measure was statistically affected until 3 years postexpansion.
By 2018, Medicaid expansion was associated with relative increases in 31 of 47 patient visit measures. Effect sizes in 2018 were greatest for visits for HIV testing (IRR = 2.02), hepatitis C testing (IRR = 1.88), mammograms (IRR = 1.45), alcohol disorder (IRR = 1.50), depression (IRR = 1.47), and other mental health (IRR = 1.77) (
P
< .01).
The first five years of Medicaid expansion were associated with increases in insurance coverage, measured quality, and visit volume among health center patients, where effects on quality of care for measures such as diabetes control were not detected until three years into the postperiod.
Findings highlight the longer term, significant role of Medicaid expansion in improving quality and in building capacity for health centers. This is particularly important in light of federal and state decisions about the future of Medicaid and extension of health center grant funding.
Agency for Healthcare Research and Quality.
Abstract Mitochondria form a cellular network of organelles, or cellular compartments, that efficiently couple nutrients to energy production in the form of ATP. As cancer cells rely heavily on ...glycolysis, historically mitochondria and the cellular pathways in place to maintain mitochondrial activities were thought to be more relevant to diseases observed in non-dividing cells such as muscles and neurons. However, more recently it has become clear that cancers rely heavily on mitochondrial activities including lipid, nucleotide and amino acid synthesis, suppression of mitochondria-mediated apoptosis as well as oxidative phosphorylation (OXPHOS) for growth and survival. Considering the variety of conditions and stresses that cancer cell mitochondria may incur such as hypoxia, reactive oxygen species and mitochondrial genome mutagenesis, we examine potential roles for a mitochondrial-protective transcriptional response known as the mitochondrial unfolded protein response (UPRmt ) in cancer cell biology.
Eukaryotic cells must accurately monitor the integrity of the mitochondrial network to overcome environmental insults and respond to physiological cues. The mitochondrial unfolded protein response ...(UPRmt) is a mitochondrial-to-nuclear signaling pathway that maintains mitochondrial proteostasis, mediates signaling between tissues, and regulates organismal aging. Aberrant UPRmt signaling is associated with a wide spectrum of disorders, including congenital diseases as well as cancers and neurodegenerative diseases. Here, we review recent research into the mechanisms underlying UPRmt signaling in Caenorhabditis elegans and discuss emerging connections between the UPRmt signaling and a translational regulation program called the ‘integrated stress response’. Further study of the UPRmt will potentially enable development of new therapeutic strategies for inherited metabolic disorders and diseases of aging.
The mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans is a transcriptional program that requires chromatin remodeling and the transcription factor ATFS-1, which is regulated by mitochondrial protein import efficiency.The UPRmt in C. elegans rewires cellular metabolism, contributes to innate immunity, mediates signaling between tissues, and regulates development and organismal aging. In mammals, the UPRmt is embedded within the integrated stress response (ISR), a program that enables selective translation of transcripts harboring upstream open reading frames.In mammals, UPRmt induction is mediated by the transcription factors CHOP; ATF4; and a functional ortholog of ATFS-1, ATF5.The kinases responsible for activating the ISR have all been implicated in maintaining mitochondrial homeostasis or responding to mitochondrial dysfunction.
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