bims-minimp 2021-10-24 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2021‒10‒24
23 papers selected by
Hanna Salmonowicz
International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

Cardiolipin remodeling enables protein crowding in the inner mitochondrial membrane.
Unfolding is the driving force for mitochondrial import and degradation of Parkinson's disease-related protein DJ-1.
An in vitro system to silence mitochondrial gene expression.
Biogenesis of Iron-Sulfur Clusters and Their Role in DNA Metabolism.
Mitochondrial Phospholipid Homeostasis Is Regulated by the i-AAA Protease PaIAP and Affects Organismic Aging.
Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress.
Loss of major nutrient sensing and signaling pathways suppresses starvation lethality in electron transport chain mutants.
ANT2 drives proinflammatory macrophage activation in obesity.
Decreasing mitochondrial RNA polymerase activity reverses biased inheritance of hypersuppressive mtDNA.
cGAS guards against chromosome end-to-end fusions during mitosis and facilitates replicative senescence.
Impairments in Brain Bioenergetics in Aging and Tau Pathology: A Chicken and Egg Situation?
Brain Region and Cell Compartment Dependent Regulation of Electron Transport System Components in Huntington's Disease Model Mice.
Cell-Free Mitochondrial DNA as a Potential Biomarker for Astronauts' Health.
eccDNAs are apoptotic products with high innate immunostimulatory activity.
Cellular Senescence and its Impact on the Circadian Clock.
Deletion of PRAK Mitigates the Mitochondria Function and Suppresses Insulin Signaling in C2C12 Myoblasts Exposed to High Glucose.
The metabolic roots of senescence: mechanisms and opportunities for intervention.
Lipid droplets diversity and functions in inflammation and immune response.
Shear stress-induced cellular senescence blunts liver regeneration through Notch-Sirt1-P21/P16 axis.
The Role of Epithelial Damage in the Pulmonary Immune Response.
Adipocytes enter the cell cycle in obesity.
How Viruses Hijack and Modify the Secretory Transport Pathway.
Structural Insights into the Human Mitochondrial Pyruvate Carrier Complexes.

EMBO J. 2021 Oct 18. e108428

Cardiolipin remodeling enables protein crowding in the inner mitochondrial membrane.

Yang Xu, Hediye Erdjument-Bromage, Colin K L Phoon, Thomas A Neubert, Mindong Ren, Michael Schlame.

  Mitochondrial cristae are extraordinarily crowded with proteins, which puts stress on the bilayer organization of lipids. We tested the hypothesis that the high concentration of proteins drives the tafazzin-catalyzed remodeling of fatty acids in cardiolipin, thereby reducing bilayer stress in the membrane. Specifically, we tested whether protein crowding induces cardiolipin remodeling and whether the lack of cardiolipin remodeling prevents the membrane from accumulating proteins. In vitro, the incorporation of large amounts of proteins into liposomes altered the outcome of the remodeling reaction. In yeast, the concentration of proteins involved in oxidative phosphorylation (OXPHOS) correlated with the cardiolipin composition. Genetic ablation of either remodeling or biosynthesis of cardiolipin caused a substantial drop in the surface density of OXPHOS proteins in the inner membrane of the mouse heart and Drosophila flight muscle mitochondria. Our data suggest that OXPHOS protein crowding induces cardiolipin remodelling and that remodeled cardiolipin supports the high concentration of these proteins in the inner mitochondrial membrane.

Keywords:  Barth syndrome; lipid-protein interaction; macromolecular crowding; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.15252/embj.2021108428
J Cell Sci. 2021 Oct 22. pii: jcs.258653. [Epub ahead of print]

Unfolding is the driving force for mitochondrial import and degradation of Parkinson's disease-related protein DJ-1.

Bruno Barros Queliconi, Waka Kojima, Mayumi Kimura, Kenichiro Imai, Chisato Udagawa, Chie Motono, Takatsugu Hirokawa, Shinya Tashiro, Jose M M Caaveiro, Kouhei Tsumoto, Koji Yamano, Keiji Tanaka, Noriyuki Matsuda.

  Diverse genes associated with familial Parkinson's disease (familial Parkinsonism) have been implicated in mitochondrial quality control. One such gene, PARK7 encodes the protein DJ-1, pathogenic mutations of which trigger its translocation from the cytosol to the mitochondrial matrix. The translocation of steady-state cytosolic proteins like DJ-1 to the mitochondrial matrix by missense mutations is rare and the underlying mechanism remains to be elucidated. Here, we show that the protein unfolding associated with various DJ-1 mutations drives its import into the mitochondrial matrix. Increasing the structural stability of these DJ-1 mutants restores cytosolic localization. Mechanistically, we show that a reduction in the structural stability of DJ-1 exposes a cryptic N-terminal mitochondrial targeting signal (MTS) including Leu10 that promotes DJ-1 import into the mitochondrial matrix for subsequent degradation. Our work describes a novel cellular mechanism for targeting a destabilized cytosolic protein to the mitochondria for degradation.

Keywords:  DJ-1; Import; Mitochondria; Parkinson's disease

DOI:  https://doi.org/10.1242/jcs.258653
Cell. 2021 Oct 11. pii: S0092-8674(21)01116-8. [Epub ahead of print]

An in vitro system to silence mitochondrial gene expression.

Luis Daniel Cruz-Zaragoza, Sven Dennerlein, Andreas Linden, Roya Yousefi, Elena Lavdovskaia, Abhishek Aich, Rebecca R Falk, Ridhima Gomkale, Thomas Schöndorf, Markus T Bohnsack, Ricarda Richter-Dennerlein, Henning Urlaub, Peter Rehling.

  The human mitochondrial genome encodes thirteen core subunits of the oxidative phosphorylation system, and defects in mitochondrial gene expression lead to severe neuromuscular disorders. However, the mechanisms of mitochondrial gene expression remain poorly understood due to a lack of experimental approaches to analyze these processes. Here, we present an in vitro system to silence translation in purified mitochondria. In vitro import of chemically synthesized precursor-morpholino hybrids allows us to target translation of individual mitochondrial mRNAs. By applying this approach, we conclude that the bicistronic, overlapping ATP8/ATP6 transcript is translated through a single ribosome/mRNA engagement. We show that recruitment of COX1 assembly factors to translating ribosomes depends on nascent chain formation. By defining mRNA-specific interactomes for COX1 and COX2, we reveal an unexpected function of the cytosolic oncofetal IGF2BP1, an RNA-binding protein, in mitochondrial translation. Our data provide insight into mitochondrial translation and innovative strategies to investigate mitochondrial gene expression.

Keywords:  IGF2BP1; antisense; mitochondria; mitochondrial ribosome; morpholino; oxidative phosphorylation; translation

DOI:  https://doi.org/10.1016/j.cell.2021.09.033
Front Cell Dev Biol. 2021 ;9 735678

Biogenesis of Iron-Sulfur Clusters and Their Role in DNA Metabolism.

Ruifeng Shi, Wenya Hou, Zhao-Qi Wang, Xingzhi Xu.

  Iron-sulfur (Fe/S) clusters (ISCs) are redox-active protein cofactors that their synthesis, transfer, and insertion into target proteins require many components. Mitochondrial ISC assembly is the foundation of all cellular ISCs in eukaryotic cells. The mitochondrial ISC cooperates with the cytosolic Fe/S protein assembly (CIA) systems to accomplish the cytosolic and nuclear Fe/S clusters maturation. ISCs are needed for diverse cellular functions, including nitrogen fixation, oxidative phosphorylation, mitochondrial respiratory pathways, and ribosome assembly. Recent research advances have confirmed the existence of different ISCs in enzymes that regulate DNA metabolism, including helicases, nucleases, primases, DNA polymerases, and glycosylases. Here we outline the synthesis of mitochondrial, cytosolic and nuclear ISCs and highlight their functions in DNA metabolism.

Keywords:  DNA metabolism; DNA repair; DNA replication; genome stability; iron-sulfur (Fe-S) clusters

DOI:  https://doi.org/10.3389/fcell.2021.735678
Cells. 2021 Oct 16. pii: 2775. [Epub ahead of print]10(10):

Mitochondrial Phospholipid Homeostasis Is Regulated by the i-AAA Protease PaIAP and Affects Organismic Aging.

Timo Löser, Aljoscha Joppe, Andrea Hamann, Heinz D Osiewacz.

  Mitochondria are ubiquitous organelles of eukaryotic organisms with a number of essential functions, including synthesis of iron-sulfur clusters, amino acids, lipids, and adenosine triphosphate (ATP). During aging of the fungal aging model Podospora anserina, the inner mitochondrial membrane (IMM) undergoes prominent morphological alterations, ultimately resulting in functional impairments. Since phospholipids (PLs) are key components of biological membranes, maintenance of membrane plasticity and integrity via regulation of PL biosynthesis is indispensable. Here, we report results from a lipidomic analysis of isolated mitochondria from P. anserina that revealed an age-related reorganization of the mitochondrial PL profile and the involvement of the i-AAA protease PaIAP in proteolytic regulation of PL metabolism. The absence of PaIAP enhances biosynthesis of characteristic mitochondrial PLs, leads to significant alterations in the acyl composition of the mitochondrial signature PL cardiolipin (CL), and induces mitophagy. These alterations presumably cause the lifespan increase of the PaIap deletion mutant under standard growth conditions. However, PaIAP is required at elevated temperatures and for degradation of superfluous CL synthase PaCRD1 during glycolytic growth. Overall, our study uncovers a prominent role of PaIAP in the regulation of PL homeostasis in order to adapt membrane plasticity to fluctuating environmental conditions as they occur in nature.

Keywords:  P. anserina; PaCRD1; PaIAP; aging; lipid metabolism; mitochondria

DOI:  https://doi.org/10.3390/cells10102775
Mol Cell. 2021 Oct 21. pii: S1097-2765(21)00798-X. [Epub ahead of print]81(20): 4191-4208.e8

Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress.

Raul Jobava, Yuanhui Mao, Bo-Jhih Guan, Di Hu, Dawid Krokowski, Chien-Wen Chen, Xin Erica Shu, Evelyn Chukwurah, Jing Wu, Zhaofeng Gao, Leah L Zagore, William C Merrick, Aleksandra Trifunovic, Andrew C Hsieh, Saba Valadkhan, Youwei Zhang, Xin Qi, Eckhard Jankowsky, Ivan Topisirovic, Donny D Licatalosi, Shu-Bing Qian, Maria Hatzoglou.

  To survive, mammalian cells must adapt to environmental challenges. While the cellular response to mild stress has been widely studied, how cells respond to severe stress remains unclear. We show here that under severe hyperosmotic stress, cells enter a transient hibernation-like state in anticipation of recovery. We demonstrate this adaptive pausing response (APR) is a coordinated cellular response that limits ATP supply and consumption through mitochondrial fragmentation and widespread pausing of mRNA translation. This pausing is accomplished by ribosome stalling at translation initiation codons, which keeps mRNAs poised to resume translation upon recovery. We further show that recovery from severe stress involves ISR (integrated stress response) signaling that permits cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. Our findings indicate that cells can respond to severe stress via a hibernation-like mechanism that preserves vital elements of cellular function under harsh environmental conditions.

Keywords:  ATF4; ISR; hypertonic; mTOR; mitochondria; neMito mRNAs; ribosome stalling; stress; translation

DOI:  https://doi.org/10.1016/j.molcel.2021.09.029
Mol Biol Cell. 2021 Oct 20. mbcE21060314

Loss of major nutrient sensing and signaling pathways suppresses starvation lethality in electron transport chain mutants.

Alisha G Lewis, Robert Caldwell, Jason V Rogers, Maria Ingaramo, Rebecca Y Wang, Ilya Soifer, David G Hendrickson, R Scott McIsaac, David Botstein, Patrick A Gibney.

The electron transport chain (ETC) is a well-studied and highly conserved metabolic pathway that produces ATP through generation of a proton gradient across the inner mitochondrial membrane coupled to oxidative phosphorylation. ETC mutations are associated with a wide array of human disease conditions and to aging-related phenotypes in a number of different organisms. In this study, we sought to better understand the role of the ETC in aging using a yeast model. A panel of ETC mutant strains that fail to survive starvation was used to isolate suppressor mutants that survive. These suppressors tend to fall into major nutrient sensing and signaling pathways, suggesting that the ETC is involved in proper starvation signaling to these pathways in yeast. These suppressors also partially restore ETC-associated gene expression and pH homeostasis defects, though it remains unclear if these phenotypes directly cause the suppression or are simply effects. This work further highlights the complex cellular network connections between metabolic pathways and signaling events in the cell, and their potential roles in aging and age-related diseases.

DOI: https://doi.org/10.1091/mbc.E21-06-0314
JCI Insight. 2021 Oct 22. pii: e147033. [Epub ahead of print]6(20):

ANT2 drives proinflammatory macrophage activation in obesity.

Jae-Su Moon, Flavia Franco da Cunha, Jin Young Huh, Alexander Yu Andreyev, Jihyung Lee, Sushil K Mahata, Felipe Cg Reis, Chanond A Nasamran, Yun Sok Lee.

  Macrophage proinflammatory activation is an important etiologic component of the development of insulin resistance and metabolic dysfunction in obesity. However, the underlying mechanisms are not clearly understood. Here, we demonstrate that a mitochondrial inner membrane protein, adenine nucleotide translocase 2 (ANT2), mediates proinflammatory activation of adipose tissue macrophages (ATMs) in obesity. Ant2 expression was increased in ATMs of obese mice compared with lean mice. Myeloid-specific ANT2-knockout (ANT2-MKO) mice showed decreased adipose tissue inflammation and improved insulin sensitivity and glucose tolerance in HFD/obesity. At the molecular level, we found that ANT2 mediates free fatty acid-induced mitochondrial permeability transition, leading to increased mitochondrial reactive oxygen species production and damage. In turn, this increased HIF-1α expression and NF-κB activation, leading to proinflammatory macrophage activation. Our results provide a previously unknown mechanism for how obesity induces proinflammatory activation of macrophages with propagation of low-grade chronic inflammation (metaflammation).

Keywords:  Diabetes; Endocrinology; Innate immunity; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.147033
PLoS Genet. 2021 Oct 19. 17(10): e1009808

Decreasing mitochondrial RNA polymerase activity reverses biased inheritance of hypersuppressive mtDNA.

Daniel Corbi, Angelika Amon.

Faithful inheritance of mitochondrial DNA (mtDNA) is crucial for cellular respiration/oxidative phosphorylation and mitochondrial membrane potential. However, how mtDNA is transmitted to progeny is not fully understood. We utilized hypersuppressive mtDNA, a class of respiratory deficient Saccharomyces cerevisiae mtDNA that is preferentially inherited over wild-type mtDNA (rho+), to uncover the factors governing mtDNA inheritance. We found that some regions of rho+ mtDNA persisted while others were lost after a specific hypersuppressive takeover indicating that hypersuppressive preferential inheritance may partially be due to active destruction of rho+ mtDNA. From a multicopy suppression screen, we found that overexpression of putative mitochondrial RNA exonuclease PET127 reduced biased inheritance of a subset of hypersuppressive genomes. This suppression required PET127 binding to the mitochondrial RNA polymerase RPO41 but not PET127 exonuclease activity. A temperature-sensitive allele of RPO41 improved rho+ mtDNA inheritance over a specific hypersuppressive mtDNA at semi-permissive temperatures revealing a previously unknown role for rho+ transcription in promoting hypersuppressive mtDNA inheritance.

DOI: https://doi.org/10.1371/journal.pgen.1009808
Protein Cell. 2021 Oct 22.

cGAS guards against chromosome end-to-end fusions during mitosis and facilitates replicative senescence.

Xiaocui Li, Xiaojuan Li, Chen Xie, Sihui Cai, Mengqiu Li, Heping Jin, Shu Wu, Jun Cui, Haiying Liu, Yong Zhao.

  As a sensor of cytosolic DNA, the role of cyclic GMP-AMP synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identify cGAS as an essential regulator in inhibiting mitotic DNA double-strand break (DSB) repair and protecting short telomeres from end-to-end fusion independent of the canonical cGAS-STING pathway. cGAS associates with telomeric/subtelomeric DNA during mitosis when TRF1/TRF2/POT1 are deficient on telomeres. Depletion of cGAS leads to mitotic chromosome end-to-end fusions predominantly occurring between short telomeres. Mechanistically, cGAS interacts with CDK1 and positions them to chromosome ends. Thus, CDK1 inhibits mitotic non-homologous end joining (NHEJ) by blocking the recruitment of RNF8. cGAS-deficient human primary cells are defective in entering replicative senescence and display chromosome end-to-end fusions, genome instability and prolonged growth arrest. Altogether, cGAS safeguards genome stability by controlling mitotic DSB repair to inhibit mitotic chromosome end-to-end fusions, thus facilitating replicative senescence.

Keywords:  DNA damage response; cGAS; chromosome end-to-end fusion; genome stability; mitosis; non-homologous end joining; telomeres

DOI:  https://doi.org/10.1007/s13238-021-00879-y
Cells. 2021 Sep 24. pii: 2531. [Epub ahead of print]10(10):

Impairments in Brain Bioenergetics in Aging and Tau Pathology: A Chicken and Egg Situation?

Amandine Grimm.

  The brain is the most energy-consuming organ of the body and impairments in brain energy metabolism will affect neuronal functionality and viability. Brain aging is marked by defects in energetic metabolism. Abnormal tau protein is a hallmark of tauopathies, including Alzheimer's disease (AD). Pathological tau was shown to induce bioenergetic impairments by affecting mitochondrial function. Although it is now clear that mutations in the tau-coding gene lead to tau pathology, the causes of abnormal tau phosphorylation and aggregation in non-familial tauopathies, such as sporadic AD, remain elusive. Strikingly, both tau pathology and brain hypometabolism correlate with cognitive impairments in AD. The aim of this review is to discuss the link between age-related decrease in brain metabolism and tau pathology. In particular, the following points will be discussed: (i) the common bioenergetic features observed during brain aging and tauopathies; (ii) how age-related bioenergetic defects affect tau pathology; (iii) the influence of lifestyle factors known to modulate brain bioenergetics on tau pathology. The findings compiled here suggest that age-related bioenergetic defects may trigger abnormal tau phosphorylation/aggregation and cognitive impairments after passing a pathological threshold. Understanding the effects of aging on brain metabolism may therefore help to identify disease-modifying strategies against tau-induced neurodegeneration.

Keywords:  Alzheimer’s disease; bioenergetics; brain glucose metabolism; cognitive stimulation; diet; exercise; lifestyle factors; mitochondria; tau protein; tauopathy

DOI:  https://doi.org/10.3390/cells10102531
Brain Sci. 2021 Sep 24. pii: 1267. [Epub ahead of print]11(10):

Brain Region and Cell Compartment Dependent Regulation of Electron Transport System Components in Huntington's Disease Model Mice.

Johannes Burtscher, Giuseppe Pepe, Federico Marracino, Luca Capocci, Susy Giova, Grégoire P Millet, Alba Di Pardo, Vittorio Maglione.

  Huntington's disease (HD) is a rare hereditary neurodegenerative disorder characterized by multiple metabolic dysfunctions including defects in mitochondrial homeostasis and functions. Although we have recently reported age-related changes in the respiratory capacities in different brain areas in HD mice, the precise mechanisms of how mitochondria become compromised in HD are still poorly understood. In this study, we investigated mRNA and protein levels of selected subunits of electron transport system (ETS) complexes and ATP-synthase in the cortex and striatum of symptomatic R6/2 mice. Our findings reveal a brain-region-specific differential expression of both nuclear and mitochondrial-encoded ETS components, indicating defects of transcription, translation and/or mitochondrial import of mitochondrial ETS components in R6/2 mouse brains.

Keywords:  Huntington’s disease; cortex; mitochondria; neurodegeneration; oxidative phosphorylation; striatum

DOI:  https://doi.org/10.3390/brainsci11101267
J Am Heart Assoc. 2021 Oct 20. e022055

Cell-Free Mitochondrial DNA as a Potential Biomarker for Astronauts' Health.

Malik Bisserier, Santhanam Shanmughapriya, Amit Kumar Rai, Carolina Gonzalez, Agnieszka Brojakowska, Venkata Naga Srikanth Garikipati, Muniswamy Madesh, Paul J Mills, Kenneth Walsh, Arsen Arakelyan, Raj Kishore, Lahouaria Hadri, David A Goukassian.

  Background Space travel-associated stressors such as microgravity or radiation exposure have been reported in astronauts after short- and long-duration missions aboard the International Space Station. Despite risk mitigation strategies, adverse health effects remain a concern. Thus, there is a need to develop new diagnostic tools to facilitate early detection of physiological stress. Methods and Results We measured the levels of circulating cell-free mitochondrial DNA in blood plasma of 14 astronauts 10 days before launch, the day of landing, and 3 days after return. Our results revealed a significant increase of cell-free mitochondrial DNA in the plasma on the day of landing and 3 days after return with vast ~2 to 355-fold interastronaut variability. In addition, gene expression analysis of peripheral blood mononuclear cells revealed a significant increase in markers of inflammation, oxidative stress, and DNA damage. Conclusions Our study suggests that cell-free mitochondrial DNA abundance might be a biomarker of stress or immune response related to microgravity, radiation, and other environmental factors during space flight.

Keywords:  astronaut; biomarker; cell‐free DNA; space medicine

DOI:  https://doi.org/10.1161/JAHA.121.022055
Nature. 2021 Oct 20.

eccDNAs are apoptotic products with high innate immunostimulatory activity.

Yuangao Wang, Meng Wang, Mohamed Nadhir Djekidel, Huan Chen, Di Liu, Frederick W Alt, Yi Zhang.

Extrachromosomal circular DNA elements (eccDNAs) have been described in the literature for several decades, and are known for their broad existence across different species1,2. However, their biogenesis and functions are largely unknown. By developing a new circular DNA enrichment method, here we purified and sequenced full-length eccDNAs with Nanopore sequencing. We found that eccDNAs map across the entire genome in a close to random manner, suggesting a biogenesis mechanism of random ligation of genomic DNA fragments. Consistent with this idea, we found that apoptosis inducers can increase eccDNA generation, which is dependent on apoptotic DNA fragmentation followed by ligation by DNA ligase 3. Importantly, we demonstrated that eccDNAs can function as potent innate immunostimulants in a manner that is independent of eccDNA sequence but dependent on eccDNA circularity and the cytosolic DNA sensor Sting. Collectively, our study not only revealed the origin, biogenesis and immunostimulant function of eccDNAs but also uncovered their sensing pathway and potential clinical implications in immune response.

DOI: https://doi.org/10.1038/s41586-021-04009-w
J Biochem. 2021 Oct 20. pii: mvab115. [Epub ahead of print]

Cellular Senescence and its Impact on the Circadian Clock.

Rezwana Ahmed, Hasan Mahmud Reza, Kazuyuki Shinohara, Yasukazu Nakahata.

  Aging is one of the greatest risk factors for chronic non-communicable diseases, and cellular senescence is one of the major causes of aging and age-related diseases. The persistent presence of senescent cells in late life seems to cause disarray in a tissue-specific manner. Aging disrupts the circadian clock system, which results in the development of many age-related diseases such as metabolic syndrome, cancer, cardiac diseases, and sleep disorders and an increased susceptibility to infections. In this review, we first discuss cellular senescence and some of its basic characteristics and detrimental roles. Then, we discuss a relatively unexplored topic on the link between cellular senescence and the circadian clock and attempt to determine whether cellular senescence could be the underlying factor for circadian clock disruption.

Keywords:  NAD+; aging; cellular senescence; circadian clock; metabolites

DOI:  https://doi.org/10.1093/jb/mvab115
Front Pharmacol. 2021 ;12 698714

Deletion of PRAK Mitigates the Mitochondria Function and Suppresses Insulin Signaling in C2C12 Myoblasts Exposed to High Glucose.

Ling Zhang, Jianguo Wang, Yu Tina Zhao, Patrycja Dubielecka, Gangjian Qin, Shougang Zhuang, Eugene Y Chin, Paul Y Liu, Ting C Zhao.

  Background: p38 regulated/activated protein kinase (PRAK) plays a crucial role in modulating cell death and survival. However, the role of PRAK in the regulation of metabolic stress remains unclear. We examined the effects of PRAK on cell survival and mitochondrial function in C2C12 myoblasts in response to high glucose stresses. Methods: PRAK of C2C12 myoblasts was knocked out by using CRISPR/Cas-9 genome editing technology. Both wild type and PRAK-/- C2C12 cells were exposed to high glucose at the concentration of 30 mmol/L to induce metabolic stress. The effect of irisin, an adipomyokine, on both wild type and PRAK-/- cells was determined to explore its relationship with RPAK. Cell viability, ATP product, glucose uptake, mitochondrial damage, and insulin signaling were assessed. Results: PRAK knockout decreased C2C12 viability in response to high glucose stress as evident by MTT assay in association with the reduction of ATP and glucose uptake. PRAK knockout enhanced apoptosis of C2C12 myoblasts in response to high glucose, consistent with an impairment in mitochondrial function, by decreasing mitochondrial membrane potential. PRAK knockout induced impairment of mitochondrial and cell damage were rescued by irisin. PRAK knockout caused decrease in phosphorylated PI3 kinase at Tyr 485, IRS-1 and AMPKα and but did not affect non-phosphorylated PI3 kinase, IRS-1 and AMPKα signaling. High glucose caused the further reduction of phosphorylated PI3 kinase, IRS-1 and AMPKα. Irisin treatment preserved phosphorylated PI3 kinase, IRS-1by rescuing PRAK in high glucose treatment. Conclusion: Our finding indicates a pivotal role of PRAK in preserving cellular survival, mitochondrial function, and high glucose stress.

Keywords:  C2C12 myoblasts; high glucose; insulin signaling; metabolic stress; mitochondria

DOI:  https://doi.org/10.3389/fphar.2021.698714
Nat Metab. 2021 Oct;3(10): 1290-1301

The metabolic roots of senescence: mechanisms and opportunities for intervention.

Christopher D Wiley, Judith Campisi.

Cellular senescence entails a permanent proliferative arrest, coupled to multiple phenotypic changes. Among these changes is the release of numerous biologically active molecules collectively known as the senescence-associated secretory phenotype, or SASP. A growing body of literature indicates that both senescence and the SASP are sensitive to cellular and organismal metabolic states, which in turn can drive phenotypes associated with metabolic dysfunction. Here, we review the current literature linking senescence and metabolism, with an eye toward findings at the cellular level, including both metabolic inducers of senescence and alterations in cellular metabolism associated with senescence. Additionally, we consider how interventions that target either metabolism or senescent cells might influence each other and mitigate some of the pro-aging effects of cellular senescence. We conclude that the most effective interventions will likely break a degenerative feedback cycle by which cellular senescence promotes metabolic diseases, which in turn promote senescence.

DOI: https://doi.org/10.1038/s42255-021-00483-8
Expert Rev Proteomics. 2021 Oct 20.

Lipid droplets diversity and functions in inflammation and immune response.

Filipe S Pereira-Dutra, Patrícia T Bozza.

  INTRODUCTION: Lipid droplets (LDs) are dynamic and evolutionary conserved lipid-enriched organelles composed of a core of neutral lipids surrounded by a monolayer of phospholipids associated with a diverse array of proteins that are cell- and stimulus-regulated. Far beyond being simply a deposit of neutral lipids, accumulating evidence demonstrate that LDs act as spatial and temporal local for lipid and protein compartmentalization and signaling organization.AREAS COVERED: This review focuses on the progress in our understanding of LD protein diversity and LD functions in the context of cell signaling and immune responses, highlighting the relationship between LD composition with the multiple roles of this organelle in immunometabolism, inflammation and host-response to infection.
EXPERT OPINION: LDs are essential platforms for various cellular processes, including metabolic regulation, cell signaling, and immune responses. The functions of LD in infection and inflammatory disease are associated with the dynamic and complexity of their proteome. Our contemporary view place LDs as critical regulators of different inflammatory and infectious diseases and key markers of leukocyte activation.

Keywords:  Lipid metabolism; eicosanoids; immunometabolism; inflammation; lipid droplets; organelle interaction; organelle proteome

DOI:  https://doi.org/10.1080/14789450.2021.1995356
Hepatology. 2021 Oct 23.

Shear stress-induced cellular senescence blunts liver regeneration through Notch-Sirt1-P21/P16 axis.

Juan-Li Duan, Bai Ruan, Ping Song, Zhi-Qiang Fang, Zhen-Sheng Yue, Jing-Jing Liu, Guo-Rui Dou, Hua Han, Lin Wang.

  BACKGROUND & AIMS: The mechanisms involved in liver regeneration after partial hepatectomy (PHx) are complicated. Cellular senescence, once linked to aging, plays a pivotal role in wound repair. However, the regulatory effects of cellular senescence on liver regeneration have not been fully elucidated.APPROACH & RESULTS: Mice subjected to PHx were analyzed 14 days after surgery. The incomplete remodeling of liver sinusoids affected shear stress-induced eNOS signaling on day 14, resulting in the accumulation of senescent liver sinusoidal endothelial cells (LSECs). Removing macrophages to augment LSEC senescence led to a malfunction of the regenerating liver. A dynamic fluctuation in Notch activity accompanied senescent LSEC accumulation during liver regeneration. Endothelial Notch activation by using Cdh5-CreERT NICeCA mice triggered LSEC senescence and senescence-associated secretory phenotype (SASP), which disrupted liver regeneration. Blocking the Notch by γ-secretase inhibitor (GSI) diminished senescence and promoted LSEC expansion. Mechanically, Notch-Hes1 signaling inhibited Sirt1 transcription by binding to its promoter region. Activation of Sirt1 by SRT1720 neutralized the up-regulation of P53, P21, and P16 caused by Notch activation, and eliminated Notch-driven LSEC senescence. Finally, Sirt1 activator promoted liver regeneration by abrogating LSEC senescence and improving sinusoid remodeling.
CONCLUSIONS: Shear stress-induced LSEC senescence driven by Notch interferes with liver regeneration after PHx. Sirt1 inhibition accelerates liver regeneration by abrogating Notch-driven senescence, providing a potential opportunity to target senescent cells and facilitate liver repair after injury.

Keywords:  Liver regeneration; Liver sinusoidal endothelial cells; Notch; Senescence; Sirt1

DOI:  https://doi.org/10.1002/hep.32209
Cells. 2021 Oct 15. pii: 2763. [Epub ahead of print]10(10):

The Role of Epithelial Damage in the Pulmonary Immune Response.

Rachel Ann Burgoyne, Andrew John Fisher, Lee Anthony Borthwick.

  Pulmonary epithelial cells are widely considered to be the first line of defence in the lung and are responsible for coordinating the innate immune response to injury and subsequent repair. Consequently, epithelial cells communicate with multiple cell types including immune cells and fibroblasts to promote acute inflammation and normal wound healing in response to damage. However, aberrant epithelial cell death and damage are hallmarks of pulmonary disease, with necrotic cell death and cellular senescence contributing to disease pathogenesis in numerous respiratory diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and coronavirus disease (COVID)-19. In this review, we summarise the literature that demonstrates that epithelial damage plays a pivotal role in the dysregulation of the immune response leading to tissue destruction and abnormal remodelling in several chronic diseases. Specifically, we highlight the role of epithelial-derived damage-associated molecular patterns (DAMPs) and senescence in shaping the immune response and assess their contribution to inflammatory and fibrotic signalling pathways in the lung.

Keywords:  COVID-19; chronic obstructive pulmonary disease (COPD); coronavirus; damage-associated molecular patterns (DAMPs); epithelial damage; idiopathic pulmonary fibrosis (IPF); lung; necroptosis; necrosis; senescence

DOI:  https://doi.org/10.3390/cells10102763
Nat Rev Endocrinol. 2021 Oct 21.

Adipocytes enter the cell cycle in obesity.

Olivia Tysoe.

DOI: https://doi.org/10.1038/s41574-021-00589-9
Cells. 2021 Sep 24. pii: 2535. [Epub ahead of print]10(10):

How Viruses Hijack and Modify the Secretory Transport Pathway.

Zubaida Hassan, Nilima Dinesh Kumar, Fulvio Reggiori, Gulfaraz Khan.

  Eukaryotic cells contain dynamic membrane-bound organelles that are constantly remodeled in response to physiological and environmental cues. Key organelles are the endoplasmic reticulum, the Golgi apparatus and the plasma membrane, which are interconnected by vesicular traffic through the secretory transport route. Numerous viruses, especially enveloped viruses, use and modify compartments of the secretory pathway to promote their replication, assembly and cell egression by hijacking the host cell machinery. In some cases, the subversion mechanism has been uncovered. In this review, we summarize our current understanding of how the secretory pathway is subverted and exploited by viruses belonging to Picornaviridae, Coronaviridae, Flaviviridae, Poxviridae, Parvoviridae and Herpesviridae families.

Keywords:  Golgi; endoplasmic reticulum; intracellular trafficking; membrane rearrangements; plasma membrane; vesicles; viruses

DOI:  https://doi.org/10.3390/cells10102535
J Chem Inf Model. 2021 Oct 19.

Structural Insights into the Human Mitochondrial Pyruvate Carrier Complexes.

Liang Xu, Clyde F Phelix, Liao Y Chen.

Pyruvate metabolism requires the mitochondrial pyruvate carrier (MPC) proteins to transport pyruvate from the intermembrane space through the inner mitochondrial membrane to the mitochondrial matrix. The lack of the atomic structures of MPC hampers the understanding of the functional states of MPC and molecular interactions with the substrate or inhibitor. Here, we develop the de novo models of human MPC complexes and characterize the conformational dynamics of the MPC heterodimer formed by MPC1 and MPC2 (MPC1/2) by computational simulations. Our results reveal that functional MPC1/2 prefers to adopt an inward-open conformation, with the carrier open to the matrix side, whereas the outward-open states are less populated. The energy barrier for pyruvate transport in MPC1/2 is low enough, and the inhibitor UK5099 blocks the pyruvate transport by stably binding to MPC1/2. Notably, consistent with experimental results, the MPC1 L79H mutation significantly alters the conformations of MPC1/2 and thus fails for substrate transport. However, the MPC1 R97W mutation seems to retain the transport activity. The present de novo models of MPC complexes provide structural insights into the conformational states of MPC complexes and mechanistic understanding of interactions between the substrate/inhibitor and MPC proteins.

DOI: https://doi.org/10.1021/acs.jcim.1c00879