bims-minimp Biomed News
on Mitochondria, innate immunity, proteostasis
Issue of 2021‒09‒19
twenty-nine papers selected by
Hanna Salmonowicz
International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences
  1. Immunology of Aging: the Birth of Inflammaging.
  2. Leaked Mitochondrial C1QBP Inhibits Activation of the DNA Sensor cGAS.
  3. CISD1 protects against atherosclerosis by suppressing lipid accumulation and inflammation via mediating Drp1.
  4. A role for mitochondrial DNA in cellular proteostasis.
  5. Targeting Adaptive Cellular Responses To Mitochondrial Bioenergetic Deficiencies In Human Disease.
  6. Decreased Mitochondrial Membrane Potential Activates the Mitochondrial Unfolded Protein Response.
  7. Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease.
  8. Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination.
  9. REST/NRSF deficiency impairs autophagy and leads to cellular senescence in neurons.
  10. Mitochondria: endosymbiont bacteria DNA sequence as a target against cancer.
  11. Mitochondrial contact site and cristae organizing system (MICOS) machinery supports heme biosynthesis by enabling optimal performance of ferrochelatase.
  12. Repeated mild traumatic brain injuries perturb the mitochondrial biogenesis via DNA methylation in the hippocampus of rat.
  13. Riboflavin transporter SLC52A1, a target of p53, suppresses cellular senescence by activating mitochondrial complex II.
  14. The mitochondrial F1FO-ATPase exploits the dithiol redox state to modulate the permeability transition pore.
  15. MKP-1 Overexpression Reduces Postischemic Myocardial Damage through Attenuation of ER Stress and Mitochondrial Damage.
  16. Mitochondrial pathway polygenic risk scores are associated with Alzheimer's Disease.
  17. Increased fidelity of protein synthesis extends lifespan.
  18. Nutrition and cellular senescence in obesity-related disorders.
  19. Lysosomal amino acid transporters as key players in inflammatory diseases.
  20. Development of a Mobile Mitochondrial Physiology Laboratory for Measuring Mitochondrial Energetics in the Field.
  21. Mitochondrial disease: Replace or edit?
  22. The neuroimmune response during stress: A physiological perspective.
  23. Healthy Aging-Relevant Goals: The Role of Person-Context Co-construction.
  24. Mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes.
  25. Cristae-dependent quality control of the mitochondrial genome.
  26. The balance between NAD+ biosynthesis and consumption in ageing.
  27. Mitochondrial-derived peptides and exercise.
  28. Circulating heat shock protein 90 (Hsp90) and autoantibodies to Hsp90 are increased in patients with atopic dermatitis.
  29. The Evolution of the Hallmarks of Aging.
  1. Clin Rev Allergy Immunol. 2021 Sep 18.
    Immunology of Aging: the Birth of Inflammaging.
    T Fulop, A Larbi, G Pawelec, A Khalil, A A Cohen, K Hirokawa, J M Witkowski, C Franceschi.
      The inflammaging concept was introduced in 2000 by Prof. Franceschi. This was an evolutionary or rather a revolutionary conceptualization of the immune changes in response to a lifelong stress. This conceptualization permitted to consider the lifelong proinflammatory process as an adaptation which could eventually lead to either beneficial or detrimental consequences. This dichotomy is influenced by both the genetics and the environment. Depending on which way prevails in an individual, the outcome may be healthy longevity or pathological aging burdened with aging-related diseases. The concept of inflammaging has also revealed the complex, systemic nature of aging. Thus, this conceptualization opens the way to consider age-related processes in their complexity, meaning that not only the process but also all counter-processes should be considered. It has also opened the way to add new concepts to the original one, leading to better understanding of the nature of inflammaging and of aging itself. Finally, it showed the way towards potential multimodal interventions involving a holistic approach to optimize the aging process towards a healthy longevity.
    Keywords:  Cytokines; Free radicals; Immunobiography; Immunosenescence; Inflammaging; Macrophages; Microbiome; Mitochondria; SASP; Signaling; Trained immunity
    DOI:  https://doi.org/10.1007/s12016-021-08899-6
  2. J Immunol. 2021 Sep 15. pii: ji2100392. [Epub ahead of print]
    Leaked Mitochondrial C1QBP Inhibits Activation of the DNA Sensor cGAS.
    Kun Song, Yakun Wu, Bishi Fu, Lingyan Wang, Wenzhuo Hao, Fang Hua, Yiwen Sun, Martin E Dorf, Shitao Li.
      Cytosolic DNA from pathogens activates the DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) that produces the second messenger, cGAMP. cGAMP triggers a signal cascade leading to type I IFN expression. Host DNA is normally restricted in the cellular compartments of the nucleus and mitochondria. Recent studies have shown that DNA virus infection triggers mitochondrial stress, leading to the release of mitochondrial DNA to the cytosol and activation of cGAS; however, the regulatory mechanism of mitochondrial DNA-mediated cGAS activation is not well elucidated. In this study, we analyzed cGAS protein interactome in mouse RAW264.7 macrophages and found that cGAS interacted with C1QBP. C1QBP predominantly localized in the mitochondria and leaked into the cytosol during DNA virus infection. The leaked C1QBP bound the NTase domain of cGAS and inhibited cGAS enzymatic activity in cells and in vitro. Overexpression of the cytosolic form of C1QBP inhibited cytosolic DNA-elicited innate immune responses and promoted HSV-1 infection. By contrast, deficiency of C1QBP led to the elevated innate immune responses and impaired HSV-1 infection. Taken together, our study suggests that C1QBP is a novel cGAS inhibitor hidden in the mitochondria.
    DOI:  https://doi.org/10.4049/jimmunol.2100392
  3. Biochem Biophys Res Commun. 2021 Aug 13. pii: S0006-291X(21)01179-7. [Epub ahead of print]577 80-88
    CISD1 protects against atherosclerosis by suppressing lipid accumulation and inflammation via mediating Drp1.
    Jinghai Hua, Zhiming Gao, Shaochun Zhong, Bocui Wei, Jianbing Zhu, Ru Ying.
      Atherosclerosis still remains the leading cause of morbidity and mortality worldwide, and deeper understanding of target signaling that protect from the atherosclerosis progression may provide novel therapeutic strategies. CDGSH iron-sulfur domain-containing protein 1 (CISD1) is a protein localized on the outer membrane of mitochondria, and plays key roles in regulating cell death and oxidative stress. However, its potential on atherosclerosis development and the underlying mechanisms are largely unknown. Here, in our study, we found markedly decreased CISD1 expression in lipid-laden THP1 macrophages. Notably, lentivirus (LV)-mediated CISD1 over-expression remarkably ameliorated lipid deposition in macrophages stimulated by ox-LDL. Furthermore, cellular total ROS and mitochondrial ROS generation, and impairment of mitochondrial membrane potential (MMP) were highly induced by ox-LDL in THP1 cells, while being considerably reversed upon CISD1 over-expression. Inflammatory response caused by ox-LDL was also significantly restrained in macrophages with CISD1 over-expression. Mechanistically, we found that CISD1 could interact with dynamin-related protein 1 (Drp1). Intriguingly, CISD1-improved mitochondrial dysfunction and inflammation in ox-LDL-treated macrophages were strongly abolished by Drp1 over-expression, indicating that Drp1 suppression might be necessary for CISD1 to perform its protective effects in vitro. In high fat diet (HFD)-fed apolipoprotein E-deficient (ApoE-/-) mice, tail vein injection of lentiviral vector expressing CISD1 remarkably decreased atherosclerotic lesion area, serum LDL cholesterol levels and triglyceride contents. Inflammatory response, cellular total and mitochondrial ROS production, and Drp1 expression levels in aorta tissues were also dramatically ameliorated in HFD-fed ApoE-/- mice, contributing to the inhibition of atherosclerosis in vivo. Therefore, improving CISD1 expression may be a novel therapeutic strategy for atherosclerosis treatment.
    Keywords:  Atherosclerosis; CISD1; Drp1; Inflammation; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.bbrc.2021.08.023
  4. Nat Rev Genet. 2021 Sep 13.
    A role for mitochondrial DNA in cellular proteostasis.
    Caroline Barranco.
      
    DOI:  https://doi.org/10.1038/s41576-021-00418-9
  5. FEBS J. 2021 Sep 12.
    Targeting Adaptive Cellular Responses To Mitochondrial Bioenergetic Deficiencies In Human Disease.
    Christopher F Bennett, Conor T Ronayne, Pere Puigserver.
      Mitochondrial dysfunction is increasingly appreciated as a central contributor to human disease. Oxidative metabolism at the mitochondrial respiratory chain produces ATP and is intricately tied to redox homeostasis and biosynthetic pathways. Metabolic stress arising from genetic mutations in mitochondrial genes and environmental factors such as malnutrition or overnutrition is perceived by the cell and leads to adaptive and maladaptive responses that can underlie pathology. Here, we will outline cellular sensors that react to alterations in energy production, organellar redox, and metabolites stemming from mitochondrial disease (MD) mutations. MD is a heterogenous group of disorders primarily defined by defects in mitochondrial oxidative phosphorylation from nuclear or mitochondrial-encoded gene mutations. Pre-clinical therapies that improve fitness of MD mouse models have been recently identified. Targeting metabolic/energetic deficiencies, maladaptive signaling processes, and hyper-oxygenation of tissues are all strategies aside from direct genetic approaches that hold therapeutic promise. A further mechanistic understanding of these curative processes as well as the identification of novel targets will significantly impact mitochondrial biology and disease research.
    Keywords:  Mitochondrial dysfunction; hypoxia; mTORC1; metabolism; mitochondrial disease; mitochondrial signaling; oxidative stress; reactive oxygen species; redox homeostasis
    DOI:  https://doi.org/10.1111/febs.16195
  6. MicroPubl Biol. 2021 ;2021
    Decreased Mitochondrial Membrane Potential Activates the Mitochondrial Unfolded Protein Response.
    Brandon J Berry, Tyrone O Nieves, Andrew P Wojtovich.
      Mitochondria are ATP-producing organelles that also signal throughout the cell. Mitochondrial protein homeostasis is regulated through membrane potential-dependent protein import and quality control signaling. The mitochondrial unfolded protein response (UPRmt) is a specific program that responds to imbalances in nuclear and mitochondrial gene expression. Mounting evidence suggests that the electrochemical gradient that powers mitochondrial function, the mitochondrial membrane potential (Δψm), is a core regulator of the UPRmt. Here we tested this notion directly by pharmacologically dissipating Δψm and monitoring UPRmt activation. We found that chemical dissipation of Δψm using FCCP indeed activated UPRmt dose-dependently in C. elegans assayed by the HSP-60::GFP reporter strain.
    DOI:  https://doi.org/10.17912/micropub.biology.000445
  7. Front Immunol. 2021 ;12 729763
    Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease.
    Alice Lepelley, Timothy Wai, Yanick J Crow.
      The immune response to viral infection involves the recognition of pathogen-derived nucleic acids by intracellular sensors, leading to type I interferon (IFN), and downstream IFN-stimulated gene, induction. Ineffective discrimination of self from non-self nucleic acid can lead to autoinflammation, a phenomenon implicated in an increasing number of disease states, and well highlighted by the group of rare genetic disorders referred to as the type I interferonopathies. To understand the pathogenesis of these monogenic disorders, and polyfactorial diseases associated with pathogenic IFN upregulation, such as systemic lupus erythematosus and dermatomyositis, it is important to define the self-derived nucleic acid species responsible for such abnormal IFN induction. Recently, attention has focused on mitochondria as a novel source of immunogenic self nucleic acid. Best appreciated for their function in oxidative phosphorylation, metabolism and apoptosis, mitochondria are double membrane-bound organelles that represent vestigial bacteria in the cytosol of eukaryotic cells, containing their own DNA and RNA enclosed within the inner mitochondrial membrane. There is increasing recognition that a loss of mitochondrial integrity and compartmentalization can allow the release of mitochondrial nucleic acid into the cytosol, leading to IFN induction. Here, we provide recent insights into the potential of mitochondrial-derived DNA and RNA to drive IFN production in Mendelian disease. Specifically, we summarize current understanding of how nucleic acids are detected as foreign when released into the cytosol, and then consider the findings implicating mitochondrial nucleic acid in type I interferonopathy disease states. Finally, we discuss the potential for IFN-driven pathology in primary mitochondrial disorders.
    Keywords:  autoinflammation; innate immunity; mitochondria; mitochondrial disease; mtDNA; mtRNA; type I interferon; type I interferonopathy
    DOI:  https://doi.org/10.3389/fimmu.2021.729763
  8. Elife. 2021 Sep 14. pii: e66278. [Epub ahead of print]10
    Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination.
    Gustavo Della Flora Nunes, Emma R Wilson, Edward Hurley, Bin He, Bert W O'Malley, Yannick Poitelon, Lawrence Wrabetz, M Laura Feltri.
      Schwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (PHB1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy in mice, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and c-Jun are continuously activated in the absence of Phb1, likely as part of the SC response to mitochondrial damage. Moreover, we demonstrate that these pathways are involved in the demyelination process, and that inhibition of mTORC1 using rapamycin partially rescues the demyelinating pathology. Therefore, we propose that mTORC1 and c-Jun may play a critical role as executioners of demyelination in the context of perturbations to SC mitochondria.
    Keywords:  mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.66278
  9. Aging Cell. 2021 Sep 14. e13471
    REST/NRSF deficiency impairs autophagy and leads to cellular senescence in neurons.
    Anna Rocchi, Emanuele Carminati, Antonio De Fusco, Jagoda Aleksandra Kowalska, Thomas Floss, Fabio Benfenati.
      During aging, brain performances decline. Cellular senescence is one of the aging drivers and a key feature of a variety of human age-related disorders. The transcriptional repressor RE1-silencing transcription factor (REST) has been associated with aging and higher risk of neurodegenerative disorders. However, how REST contributes to the senescence program and functional impairment remains largely unknown. Here, we report that REST is essential to prevent the senescence phenotype in primary mouse neurons. REST deficiency causes failure of autophagy and loss of proteostasis, increased oxidative stress, and higher rate of cell death. Re-establishment of autophagy reverses the main hallmarks of senescence. Our data indicate that REST has a protective role in physiological aging by regulating the autophagic flux and the senescence program in neurons, with implications for neurological disorders associated with aging.
    Keywords:  REST/NRSF; autophagy; mitochondria; neurons; oxidative stress; rapamycin; senescence; trehalose
    DOI:  https://doi.org/10.1111/acel.13471
  10. Cancer Sci. 2021 Sep 17.
    Mitochondria: endosymbiont bacteria DNA sequence as a target against cancer.
    Hiroki Nagase, Takayoshi Watanabe, Nobuko Koshikawa, Seigi Yamamoto, Keizo Takenaga, Jason Lin.
      As the energy factory for the cell, the mitochondrion, through its role of adenosine triphosphate production by oxidative phosphorylation, can be regarded as the guardian of well-regulated cellular metabolism; the integrity of mitochondrial functions, however, is particularly vulnerable in cancer due to the lack of superstructures such as histone and lamina folds to protect the mitochondrial genome from unintended exposure, which consequently elevates risks of mutation. In cancer, mechanisms responsible for enforcing quality control surveillance for identifying and eliminating defective mitochondria is often poorly regulated, and certain uneliminated mitochondrial DNA (mtDNA) mutations and polymorphisms can be advantageous for the proliferation, progression and metastasis of tumor cells. Such pathogenic mtDNA aberrations are likely to increase and occasionally be homoplasmic in cancer cells and, intriguingly, in normal cells in the proximity of tumor microenvironments (TME) as well. Distinct characteristics of these abnormalities in mtDNA may provide a new path for cancer therapy. Here we discuss a promising novel therapeutic strategy, utilizing the sequence-specific properties of pyrrole-imidazole polyamide-triphenylphosphonium conjugates, against cancer for clearing abnormal mtDNA by reactivating mitochondrial quality control surveillance.
    Keywords:  Age-related disorder; Anti-cancer therapy; Apoptosis; Autophagy; BCL family; Exocytosis; Mitochondria; Mitochondrial disease; Mitochondrial quality control (MQC); Mitophagy; Mutation; Polymorphism; Pyrrole-imidazole polyamide; Reactive oxygen species (ROS); Senescence; Triphenylphosphonium (TPP); mtDNA
    DOI:  https://doi.org/10.1111/cas.15143
  11. Redox Biol. 2021 Sep 10. pii: S2213-2317(21)00284-6. [Epub ahead of print]46 102125
    Mitochondrial contact site and cristae organizing system (MICOS) machinery supports heme biosynthesis by enabling optimal performance of ferrochelatase.
    Jonathan V Dietz, Mathilda M Willoughby, Robert B Piel, Teresa A Ross, Iryna Bohovych, Hannah G Addis, Jennifer L Fox, William N Lanzilotta, Harry A Dailey, James A Wohlschlegel, Amit R Reddi, Amy E Medlock, Oleh Khalimonchuk.
      Heme is an essential cofactor required for a plethora of cellular processes in eukaryotes. In metazoans the heme biosynthetic pathway is typically partitioned between the cytosol and mitochondria, with the first and final steps taking place in the mitochondrion. The pathway has been extensively studied and its biosynthetic enzymes structurally characterized to varying extents. Nevertheless, understanding of the regulation of heme synthesis and factors that influence this process in metazoans remains incomplete. Therefore, we investigated the molecular organization as well as the physical and genetic interactions of the terminal pathway enzyme, ferrochelatase (Hem15), in the yeast Saccharomyces cerevisiae. Biochemical and genetic analyses revealed dynamic association of Hem15 with Mic60, a core component of the mitochondrial contact site and cristae organizing system (MICOS). Loss of MICOS negatively impacts Hem15 activity, affects the size of the Hem15 high-mass complex, and results in accumulation of reactive and potentially toxic tetrapyrrole precursors that may cause oxidative damage. Restoring intermembrane connectivity in MICOS-deficient cells mitigates these cytotoxic effects. These data provide new insights into how heme biosynthetic machinery is organized and regulated, linking mitochondrial architecture-organizing factors to heme homeostasis.
    Keywords:  Ferrochelatase; Heme; MICOS; Mitochondria; Yeast
    DOI:  https://doi.org/10.1016/j.redox.2021.102125
  12. Mitochondrion. 2021 Sep 08. pii: S1567-7249(21)00119-7. [Epub ahead of print]
    Repeated mild traumatic brain injuries perturb the mitochondrial biogenesis via DNA methylation in the hippocampus of rat.
    Nagalakshmi Balasubramanian, Gouri Jadhav, Amul J Sakharkar.
      Mitochondrial biogenesis in the brain is impaired in various neurological disorders including traumatic brain injury (TBI). The long-lasting effects of TBI may be, in part, attributed to epigenetic mechanisms such as DNA methylation. However, the role of DNA methylation on regulatory elements of nuclear and mitochondrial genome in mitochondrial biogenesis is not known. We examined the epigenetic regulation of mitochondrial transcription factor A (TFAM), and further probed its implications in mitochondrial dysfunction in the hippocampus of rats subjected to repeated mild TBI (rMTBI) using weight drop injury paradigm. rMTBI-induced hypermethylation at TFAM promoter resulted in deficits in its protein levels in mitochondria after immediate (48 h) and protracted (30 d) time points. Further, rMTBI also caused hypomethylation of mitochondrial DNA (mtDNA) promoters (HSP1 and HSP2), which further culminated into low binding of TFAM. rMTBI-induced changes weakened mitochondrial biogenesis in terms of reduced mtDNA-encoded rRNA, mRNA, and protein levels leading to shortages of ATP. To verify the potential role of mtDNA methylation in rMTBI-induced persistent mitochondrial dysfunction, rMTBI-induced rats were treated with methionine, a methyl donor. Methionine treatment restored the methylation levels on HSP1 and HSP2 resulting in efficient binding of TFAM and normalized the rRNA, mRNA, and protein levels. These findings suggest the crucial role of DNA methylation at nuclear and mitochondrial promoter regions in mitochondrial gene expression and ATP activity in the hippocampus after rMTBI.
    Keywords:  DNA methylation; Heavy strand promoter; Mild traumatic brain injury; Mitochondrial biogenesis; Mitochondrial transcription factor A; mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.mito.2021.09.001
  13. Mol Biol Cell. 2021 Sep 15. mbcE21050262
    Riboflavin transporter SLC52A1, a target of p53, suppresses cellular senescence by activating mitochondrial complex II.
    Taiki Nagano, Yuto Awai, Shione Kuwaba, Taiichi Osumi, Kentaro Mio, Tetsushi Iwasaki, Shinji Kamada.
      Cellular senescence is a state of permanent proliferative arrest induced by a variety of stresses, such as DNA damage. The transcriptional activity of p53 has been known to be essential for senescence induction. It remains unknown, however, whether among the downstream genes of p53, there is a gene that has anti-senescence function. Our recent studies have indicated that the expression of SLC52A1 (also known as GPR172B/RFVT1), a riboflavin transporter, is upregulated specifically in senescent cells depending on p53, but the relationship between senescence and SLC52A1 or riboflavin has not been described. Here, we examined the role of SLC52A1 in senescence. We found that knockdown of SLC52A1 promoted senescence phenotypes induced by DNA damage in tumor and normal cells. The senescence suppressive-action of SLC52A1 was dependent on its riboflavin transport activity. Furthermore, elevation of intracellular riboflavin led to activation of mitochondrial membrane potential (MMP) mediated by the mitochondrial electron transport chain complex II. Finally, the SLC52A1-dependent activation of MMP inhibited the AMPK-p53 pathway, a central mediator of mitochondria dysfunction-related senescence. These results suggest that SLC52A1 contributes to suppress senescence through the uptake of riboflavin and acts downstream of p53 as a negative feedback mechanism to limit aberrant senescence induction.
    DOI:  https://doi.org/10.1091/mbc.E21-05-0262
  14. Arch Biochem Biophys. 2021 Sep 11. pii: S0003-9861(21)00276-9. [Epub ahead of print] 109027
    The mitochondrial F1FO-ATPase exploits the dithiol redox state to modulate the permeability transition pore.
    Cristina Algieri, Fabiana Trombetti, Alessandra Pagliarani, Vittoria Ventrella, Salvatore Nesci.
      The dithiol reagents phenylarsine oxide (PAO) and dibromobimane (DBrB) have opposite effects on the F1FO-ATPase activity. PAO 20% increases ATP hydrolysis at 50 μM when the enzyme activity is activated by the natural cofactor Mg2+ and at 150 μM when it is activated by Ca2+. The PAO-driven F1FO-ATPase activation is reverted to the basal activity by 50 μM dithiothreitol (DTE). Conversely, 300 μM DBrB decreases the F1FO-ATPase activity by 25% when activated by Mg2+ and by 50% when activated by Ca2+. In both cases, the F1FO-ATPase inhibition by DBrB is insensitive to DTE. The mitochondrial permeability transition pore (mPTP) formation, related to the Ca2+-dependent F1FO-ATPase activity, is stimulated by PAO and desensitized by DBrB. Since PAO and DBrB apparently form adducts with different cysteine couples, the results highlight the crucial role of cross-linking of vicinal dithiols on the F1FO-ATPase, with (ir)reversible redox states, in the mPTP modulation.
    Keywords:  F(1)F(O)-ATPase; Mitochondria; Post-translational modification; Thiols; mPTP
    DOI:  https://doi.org/10.1016/j.abb.2021.109027
  15. Oxid Med Cell Longev. 2021 ;2021 8905578
    MKP-1 Overexpression Reduces Postischemic Myocardial Damage through Attenuation of ER Stress and Mitochondrial Damage.
    Xiaoling Hou, Lijun Li, Si Chen, Cheng Ge, Mingzhi Shen, Zhenhong Fu.
      Mitochondrial dysfunction and endoplasmic reticulum (ER) stress contribute to postischemic myocardial damage, but the upstream regulatory mechanisms have not been identified. In this study, we analyzed the role of mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) in the regulation of mitochondrial function and ER stress in hypoxic cardiomyocytes. Our results show that MKP-1 overexpression sustains viability and reduces hypoxia-induced apoptosis among H9C2 cardiomyocytes. MKP-1 overexpression attenuates ER stress and expression of ER stress genes and improves mitochondrial function in hypoxia-treated H9C2 cells. MKP-1 overexpression also increases ATP production and mitochondrial respiration and attenuates mitochondrial oxidative damage in hypoxic cardiomyocytes. Moreover, our results demonstrate that ERK and JNK are the downstream signaling targets of MKP-1 and that MKP-1 overexpression activates ERK, while it inhibits JNK. Inhibition of ERK reduces the ability of MKP-1 to preserve mitochondrial function and ER homeostasis in hypoxic cardiomyocytes. These results show that MKP-1 plays an essential role in the regulation of mitochondrial function and ER stress in hypoxic H9C2 cardiomyocytes through normalization of the ERK pathway and suggest that MKP-1 may serve as a novel target for the treatment of postischemic myocardial injury.
    DOI:  https://doi.org/10.1155/2021/8905578
  16. Neurobiol Aging. 2021 Aug 18. pii: S0197-4580(21)00259-1. [Epub ahead of print]
    Mitochondrial pathway polygenic risk scores are associated with Alzheimer's Disease.
    Devashi Paliwal, Tim W McInerney, Judy Pa, Russell H Swerdlow, Simon Easteal, Shea J Andrews, .
      Genetic, animal and epidemiological studies involving biomolecular and clinical endophenotypes implicate mitochondrial dysfunction in Alzheimer's disease (AD) pathogenesis. Polygenic risk scores (PRS) provide a novel approach to assess biological pathway-associated disease risk by combining the effects of variation at multiple, functionally related genes. We investigated the associations of PRS for genes involved in 12 mitochondrial pathways (pathway-PRS) with AD in 854 participants from Alzheimer's Disease Neuroimaging Initiative. Pathway-PRS for the nuclear-encoded mitochondrial genome (OR: 1.99 [95% Cl: 1.70, 2.35]) and three mitochondrial pathways is significantly associated with increased AD risk: (i) response to oxidative stress (OR: 2.01 [95% Cl: 1.71, 2.38]); (ii) mitochondrial transport (OR: 1.81 [95% Cl: 1.55, 2.13]); (iii) hallmark oxidative phosphorylation (OR: 1.22 [95% Cl: 1.06, 1.40]. Therapeutic approaches targeting these pathways may have the potential for modifying AD pathogenesis. Further investigation is required to establish a causal role for these pathways in AD pathology.
    Keywords:  Alzheimer's disease; Cognitive decline; Mitochondria; Mitochondrial dysfunction; Polygenic risk scores
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2021.08.005
  17. Cell Metab. 2021 Sep 08. pii: S1550-4131(21)00417-4. [Epub ahead of print]
    Increased fidelity of protein synthesis extends lifespan.
    Victoria Eugenia Martinez-Miguel, Celia Lujan, Tristan Espie-Caullet, Daniel Martinez-Martinez, Saul Moore, Cassandra Backes, Suam Gonzalez, Evgeniy R Galimov, André E X Brown, Mario Halic, Kazunori Tomita, Charalampos Rallis, Tobias von der Haar, Filipe Cabreiro, Ivana Bjedov.
      Loss of proteostasis is a fundamental process driving aging. Proteostasis is affected by the accuracy of translation, yet the physiological consequence of having fewer protein synthesis errors during multi-cellular organismal aging is poorly understood. Our phylogenetic analysis of RPS23, a key protein in the ribosomal decoding center, uncovered a lysine residue almost universally conserved across all domains of life, which is replaced by an arginine in a small number of hyperthermophilic archaea. When introduced into eukaryotic RPS23 homologs, this mutation leads to accurate translation, as well as heat shock resistance and longer life, in yeast, worms, and flies. Furthermore, we show that anti-aging drugs such as rapamycin, Torin1, and trametinib reduce translation errors, and that rapamycin extends further organismal longevity in RPS23 hyperaccuracy mutants. This implies a unified mode of action for diverse pharmacological anti-aging therapies. These findings pave the way for identifying novel translation accuracy interventions to improve aging.
    Keywords:  RPS23; aging; archaea; mTOR; protein synthesis; proteostasis; ribosome; translation; translation accuracy; translation fidelity
    DOI:  https://doi.org/10.1016/j.cmet.2021.08.017
  18. J Nutr Biochem. 2021 Sep 10. pii: S0955-2863(21)00281-3. [Epub ahead of print] 108861
    Nutrition and cellular senescence in obesity-related disorders.
    Teresa Rubio-Tomás, Ascensión Rueda-Robles, Julio Plaza-Díaz, Ana I Álvarez-Mercado.
      Adequate nutrition is vital for immune homeostasis. However, the incidence of obesity is increasing worldwide due to the adoption of the Western diet and a sedentary lifestyle. Obesity is associated with chronic inflammation which alters the function of adipose tissue, liver, pancreas, and the nervous system. Inflammation is related to cellular senescence, distinguished by irreversible cell cycle arrest. Senescent cells secrete the senescence-associated secretory phenotype (SASP) which contains pro-inflammatory factors. Targeting processes in senescence might have a salutary approach to obesity. The present review highlights the impact of an unhealthy diet on tissues affected by obesity, and the mechanisms that promote the consequent inflammation and senescence.
    Keywords:  aging; diet; inflammation; microbiota obesity; senescence
    DOI:  https://doi.org/10.1016/j.jnutbio.2021.108861
  19. Int Immunol. 2021 Sep 11. pii: dxab069. [Epub ahead of print]
    Lysosomal amino acid transporters as key players in inflammatory diseases.
    Noriko Toyama-Sorimachi, Toshihiko Kobayashi.
      Controlling inflammation can alleviate immune-mediated, lifestyle-related and neurodegenerative diseases. The endolysosome system plays critical roles in inflammatory responses. Endolysosomes function as signal transduction hubs to convert various environmental danger signals into gene expression, enabling metabolic adaptation of immune cells and efficient orchestration of inflammation. Solute carrier family 15 member 3 (SLC15A3) and member 4 (SLC15A4) are endolysosome-resident amino acid transporters that are preferentially expressed in immune cells. These transporters play essential roles in signal transduction through endolysosomes, and the loss of either transporter can alleviate multiple inflammatory diseases because of perturbed endolysosome-dependent signaling events, including inflammatory and metabolic signaling. Here, we summarize the findings leading to a proof-of-concept for anti-inflammatory strategies based on targeting SLC15 transporters.
    Keywords:  amino acid transporter; endolysosome systems; immunometabolism; inflammatory signals; innate immune cells
    DOI:  https://doi.org/10.1093/intimm/dxab069
  20. J Vis Exp. 2021 Aug 27.
    Development of a Mobile Mitochondrial Physiology Laboratory for Measuring Mitochondrial Energetics in the Field.
    Hailey A Parry, Kang Nian Yap, Geoffrey E Hill, Wendy R Hood, L Bruce Gladden, Michael Eddy, Andreas N Kavazis.
      Mitochondrial energetics is a central theme in animal biochemistry and physiology, with researchers using mitochondrial respiration as a metric to investigate metabolic capability. To obtain the measures of mitochondrial respiration, fresh biological samples must be used, and the entire laboratory procedure must be completed within approximately 2 h. Furthermore, multiple pieces of specialized equipment are required to perform these laboratory assays. This creates a challenge for measuring mitochondrial respiration in the tissues of wild animals living far from physiology laboratories as live tissue cannot be preserved for very long after collection in the field. Moreover, transporting live animals over long distances induces stress, which can alter mitochondrial energetics. This manuscript introduces the Auburn University (AU) MitoMobile, a mobile mitochondrial physiology laboratory that can be taken into the field and used on-site to measure mitochondrial metabolism in tissues collected from wild animals. The basic features of the mobile laboratory and the step-by-step methods for measuring isolated mitochondrial respiration rates are presented. Additionally, the data presented validate the success of outfitting the mobile mitochondrial physiology laboratory and making mitochondrial respiration measurements. The novelty of the mobile laboratory lies in the ability to drive to the field and perform mitochondrial measurements on the tissues of animals captured on site.
    DOI:  https://doi.org/10.3791/62956
  21. Science. 2021 Sep 10. 373(6560): 1200-1201
    Mitochondrial disease: Replace or edit?
    Eli Y Adashi, Donald S Rubenstein, Jim A Mossman, Eric A Schon, I Glenn Cohen.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/science.abg0491
  22. Immunity. 2021 Sep 14. pii: S1074-7613(21)00357-5. [Epub ahead of print]54(9): 1933-1947
    The neuroimmune response during stress: A physiological perspective.
    Hedva Haykin, Asya Rolls.
      Stress is an essential adaptive response that enables the organism to cope with challenges and restore homeostasis. Different stressors require distinctive corrective responses in which immune cells play a critical role. Hence, effects of stress on immunity may vary accordingly. Indeed, epidemiologically, stress can induce either inflammation or immune suppression in an organism. However, in the absence of a conceptual framework, these effects appear chaotic, leading to confusion. Here, we examine how stressor diversity is imbedded in the neuroimmune axis. Stressors differ in the brain patterns they induce, diversifying the neuronal and endocrine mediators dispatched to the periphery and generating a wide range of potential immune effects. Uncovering this complexity and diversity of the immune response to different stressors will allow us to understand the involvement of stress in pathological conditions, identify ways to modulate it, and even harness the therapeutic potential embedded in an adaptive response to stress.
    DOI:  https://doi.org/10.1016/j.immuni.2021.08.023
  23. J Gerontol B Psychol Sci Soc Sci. 2021 Sep 13. 76(Supplement_2): S181-S190
    Healthy Aging-Relevant Goals: The Role of Person-Context Co-construction.
    Hans-Werner Wahl, Christiane A Hoppmann, Nilam Ram, Denis Gerstorf.
      OBJECTIVES: This article considers how individuals' motivation for healthy aging manifests within the myriad of different contexts that older adults are embedded in as they move through later life.METHODS: Drawing on the concept of co-construction, we argue that persons and contexts both contribute to the emergence, maintenance, and disengagement from healthy aging relevant goals in adulthood and old age.
    RESULTS: To promote the understanding of such co-constructive dynamics, we propose four conceptual refinements of previous healthy aging models. First, we outline various different, often multidirectional, ways in which persons and contexts conjointly contribute to how people set, pursue, and disengage from health goals. Second, we promote consideration of context as involving unique, shared, and interactive effects of socio-economic, social, physical, care/service, and technology dimensions. Third, we highlight how the relevance, utility, and nature of these context dimensions and their role in co-constructing health goals change as individuals move through the Third Age, the Fourth Age, and a terminal stages of life. Finally, we suggest that these conceptual refinements be linked to established (motivational) theories of lifespan development and aging.
    DISCUSSIONS: In closing, we outline a set of research questions that promise to advance our understanding of the mechanisms by which contexts and aging persons co-construct healthy aging relevant goals and elaborate on the applied significance of this approach for common public health practices.
    Keywords:  CODA model of context; Fourth Age; Goals in healthy aging; Terminal stage; Third Age
    DOI:  https://doi.org/10.1093/geronb/gbab089
  24. Cell Rep. 2021 Sep 14. pii: S2211-1247(21)01173-6. [Epub ahead of print]36(11): 109724
    Mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes.
    Byung Soo Kong, Se Hee Min, Changhan Lee, Young Min Cho.
      
    DOI:  https://doi.org/10.1016/j.celrep.2021.109724
  25. Sci Adv. 2021 Sep 03. 7(36): eabi8886
    Cristae-dependent quality control of the mitochondrial genome.
    Christopher Jakubke, Rodaria Roussou, Andreas Maiser, Christina Schug, Felix Thoma, David Bunk, David Hörl, Heinrich Leonhardt, Peter Walter, Till Klecker, Christof Osman.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciadv.abi8886
  26. Mech Ageing Dev. 2021 Sep 09. pii: S0047-6374(21)00141-X. [Epub ahead of print] 111569
    The balance between NAD+ biosynthesis and consumption in ageing.
    Øyvind Strømland, Joseph Diab, Eugenio Ferrario, Lars J Sverkeli, Mathias Ziegler.
      Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme in redox reactions. NAD+ is also important in cellular signalling as it is consumed by PARPs, SARM1, sirtuins and CD38. Cellular NAD+ levels regulate several essential processes including DNA repair, immune cell function, senescence, and chromatin remodelling. Maintenance of these cellular processes is important for healthy ageing and lifespan. Interestingly, the levels of NAD+ decline during ageing in several organisms, including humans. Declining NAD+ levels have been linked to several age-related diseases including various metabolic diseases and cognitive decline. Decreasing tissue NAD+ concentrations have been ascribed to an imbalance between biosynthesis and consumption of the dinucleotide, resulting from, for instance, reduced levels of the rate limiting enzyme NAMPT along with an increased activation state of the NAD+-consuming enzymes PARPs and CD38. The progression of some age-related diseases can be halted or reversed by therapeutic augmentation of NAD+ levels. NAD+ metabolism has therefore emerged as a potential target to ameliorate age-related diseases. The present review explores how ageing affects NAD+ metabolism and current approaches to reverse the age-dependent decline of NAD+.
    Keywords:  NAD biosynthesis; NAD metabolism; PARP; Sirtuins; ageing
    DOI:  https://doi.org/10.1016/j.mad.2021.111569
  27. Biochim Biophys Acta Gen Subj. 2021 Sep 11. pii: S0304-4165(21)00170-7. [Epub ahead of print] 130011
    Mitochondrial-derived peptides and exercise.
    Jonathan S T Woodhead, Troy L Merry.
      Acute exercise, and in particular aerobic exercise, increases skeletal muscle energy demand causing mitochondrial stress, and mitochondrial-related adaptations which are a hallmark of exercise training. Given that mitochondria are central players in the exercise response, it is imperative that they have networks that can communicate their status both intra- and inter-cellularly. Peptides encoded by short open-reading frames within mitochondrial DNA, mitochondrial-derived peptides (MDPs), have been suggested to form a newly recognised branch of this retrograde signalling cascade that contribute to coordinating the adaptive response to regular exercise. Here we summarise the recent evidence that acute high intensity exercise in humans can increase concentrations of the MDPs humanin and MOTS-c in skeletal muscle and plasma, and speculate on the mechanisms controlling MDP responses to exercise stress. Evidence that exercise training results in chronic changes in MDP expression within tissues and the circulation is conflicting and may depend on the mode, duration, intensity of training plan and participant characteristics. Further research is required to define the effect of these variables on MDPs and to determine whether MDPs other than MOTS-c have exercise mimetic properties. MOTS-c treatment of young and aged mice improves exercise capacity/performance and leads to adaptions that are similar to that of being physically active (weight loss, increased antioxidant capacity and improved insulin sensitivity), however, studies utilising a MOTS-c inactivating genetic variant or combination of exercise + MOTS-c treatment in mice suggest that there are distinct and overlapping pathways through which exercise and MOTS-c evoke metabolic benefits. Overall, MOTS-c, and potentially other MDPs, may be exercise-sensitive myokines and further work is required to define inter- and intra-tissue targets in an exercise context.
    Keywords:  Cellular signalling; Hormesis; Mitochondria; Muscle; Physical activity; ROS
    DOI:  https://doi.org/10.1016/j.bbagen.2021.130011
  28. Cell Stress Chaperones. 2021 Sep 16.
    Circulating heat shock protein 90 (Hsp90) and autoantibodies to Hsp90 are increased in patients with atopic dermatitis.
    Krzysztof Sitko, Marta Bednarek, Jagoda Mantej, Magdalena Trzeciak, Stefan Tukaj.
      Atopic dermatitis (AD) is one of the most common chronic inflammatory dermatoses characterized by persistent itching and recurrent eczematous lesions. While the primary events and key drivers of AD are topics of ongoing debate, cutaneous inflammation due to inappropriate IgE (auto)antibody-related immune reactions is frequently considered. Highly conserved and immunogenic heat shock protein 90 (Hsp90), a key intra- and extracellular chaperone, can activate the immune response driving the generation of circulating anti-Hsp90 autoantibodies that are found to be elevated in several autoimmune disorders. Here, for the first time, we observed that serum levels of Hsp90 and anti-Hsp90 IgE autoantibodies are significantly elevated (p < 0.0001) in AD patients (n = 29) when compared to age- and gender-matched healthy controls (n = 70). We revealed a positive correlation (0.378, p = 0.042) between serum levels of Hsp90 and the severity of AD assessed by Scoring Atopic Dermatitis (SCORAD). In addition, seropositivity for anti-Hsp90 IgE has been found in 48.27% of AD patients and in 2.85% of healthy controls. Although further studies on a larger group of patients are needed to confirm presented data, our results suggest that extracellular Hsp90 and autoantibodies to Hsp90 deserve attention in the study of the mechanisms that promote the development and/or maintenance of atopic dermatitis.
    Keywords:  Allergy; Atopic dermatitis, AD; Autoantibodies; Autoimmunity; Heat shock proteins, Hsps; Hsp90; IgE
    DOI:  https://doi.org/10.1007/s12192-021-01238-w
  29. Front Genet. 2021 ;12 693071
    The Evolution of the Hallmarks of Aging.
    Maël Lemoine.
      The evolutionary theory of aging has set the foundations for a comprehensive understanding of aging. The biology of aging has listed and described the "hallmarks of aging," i.e., cellular and molecular mechanisms involved in human aging. The present paper is the first to infer the order of appearance of the hallmarks of bilaterian and thereby human aging throughout evolution from their presence in progressively narrower clades. Its first result is that all organisms, even non-senescent, have to deal with at least one mechanism of aging - the progressive accumulation of misfolded or unstable proteins. Due to their cumulation, these mechanisms are called "layers of aging." A difference should be made between the first four layers of unicellular aging, present in some unicellular organisms and in all multicellular opisthokonts, that stem and strike "from the inside" of individual cells and span from increasingly abnormal protein folding to deregulated nutrient sensing, and the last four layers of metacellular aging, progressively appearing in metazoans, that strike the cells of a multicellular organism "from the outside," i.e., because of other cells, and span from transcriptional alterations to the disruption of intercellular communication. The evolution of metazoans and eumetazoans probably solved the problem of aging along with the problem of unicellular aging. However, metacellular aging originates in the mechanisms by which the effects of unicellular aging are kept under control - e.g., the exhaustion of stem cells that contribute to replace damaged somatic cells. In bilaterians, additional functions have taken a toll on generally useless potentially limited lifespan to increase the fitness of organisms at the price of a progressively less efficient containment of the damage of unicellular aging. In the end, this picture suggests that geroscience should be more efficient in targeting conditions of metacellular aging rather than unicellular aging itself.
    Keywords:  aging; bilaterians; evolution; geroscience; metacellular aging; unicellular aging
    DOI:  https://doi.org/10.3389/fgene.2021.693071
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