bims-minimp 2022-07-10 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2022–07–10
seventeen papers selected by
Hanna Salmonowicz, International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

Genetically controlled mtDNA deletions prevent ROS damage by arresting oxidative phosphorylation.
Modulating mitofusins to control mitochondrial function and signaling.
Spautin-1 inhibits mitochondrial complex I and leads to suppression of the unfolded protein response and cell survival during glucose starvation.
Mitochondrial GCN5L1 regulates cytosolic redox state and hepatic gluconeogenesis via glycerol phosphate shuttle GPD2.
Amino acid catabolism regulates hematopoietic stem cell proteostasis via a GCN2-eIF2α axis.
Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation.
Overexpression of MRX9 impairs processing of RNAs encoding mitochondrial oxidative phosphorylation factors COB and COX1 in yeast.
Mitochondria-targeted senotherapeutic interventions.
Mitochondria: intracellular sentinels of infections.
Mechanisms of mitochondrial respiratory adaptation.
Mitochondria - Nucleus communication in neurodegenerative disease. Who talks first, who talks louder?
Emerging role of mitochondrial DAMPs, aberrant mitochondrial dynamics and anomalous mitophagy in gut mucosal pathogenesis.
Senescence: An Identity Crisis Originating from Deep Within the Nucleus.
Mitochondria as Cellular and Organismal Signaling Hubs.
Tetracycline-induced mitohormesis mediates disease tolerance against influenza.
Mitoribosomal Deregulation Drives Senescence via TPP1-Mediated Telomere Deprotection.
Uncovering the source of mitochondrial superoxide in pro-inflammatory macrophages: Insights from immunometabolism.

Elife. 2022 Jul 08. pii: e76095. [Epub ahead of print]11

Genetically controlled mtDNA deletions prevent ROS damage by arresting oxidative phosphorylation.

Simon Stenberg, Jing Li, Arne B Gjuvsland, Karl Persson, Erik Demitz-Helin, Carles González Peña, Jia-Xing Yue, Ciaran Gilchrist, Timmy Ärengård, Payam Ghiaci, Lisa Larsson-Berghund, Martin Zackrisson, Silvana Smits, Johan Hallin, Johanna L Höög, Mikael Molin, Gianni Liti, Stig W Omholt, Jonas Warringer.

  Deletion of mitochondrial DNA in eukaryotes is currently attributed to rare accidental events associated with mitochondrial replication or repair of double-strand breaks. We report the discovery that yeast cells arrest harmful intramitochondrial superoxide production by shutting down respiration through genetically controlled deletion of mitochondrial oxidative phosphorylation genes. We show that this process critically involves the antioxidant enzyme superoxide dismutase 2 and two-way mitochondrial-nuclear communication through Rtg2 and Rtg3. While mitochondrial DNA homeostasis is rapidly restored after cessation of a short-term superoxide stress, long-term stress causes maladaptive persistence of the deletion process, leading to complete annihilation of the cellular pool of intact mitochondrial genomes and irrevocable loss of respiratory ability. This shows that oxidative stress-induced mitochondrial impairment may be under strict regulatory control. If the results extend to human cells, the results may prove to be of etiological as well as therapeutic importance with regard to age-related mitochondrial impairment and disease.

Keywords:  S. cerevisiae; cell biology; genetics; genomics

DOI:  https://doi.org/10.7554/eLife.76095
Nat Commun. 2022 Jul 07. 13(1): 3775

Modulating mitofusins to control mitochondrial function and signaling.

Emmanouil Zacharioudakis, Bogos Agianian, Vasantha Kumar Mv, Nikolaos Biris, Thomas P Garner, Inna Rabinovich-Nikitin, Amanda T Ouchida, Victoria Margulets, Lars Ulrik Nordstrøm, Joel S Riley, Igor Dolgalev, Yun Chen, Andre J H Wittig, Ryan Pekson, Chris Mathew, Peter Wei, Aristotelis Tsirigos, Stephen W G Tait, Lorrie A Kirshenbaum, Richard N Kitsis, Evripidis Gavathiotis.

Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Mitofusins are activated by conformational changes and subsequently oligomerize to enable mitochondrial fusion. Here, we identify small molecules that directly increase or inhibit mitofusins activity by modulating mitofusin conformations and oligomerization. We use these small molecules to better understand the role of mitofusins activity in mitochondrial fusion, function, and signaling. We find that mitofusin activation increases, whereas mitofusin inhibition decreases mitochondrial fusion and functionality. Remarkably, mitofusin inhibition also induces minority mitochondrial outer membrane permeabilization followed by sub-lethal caspase-3/7 activation, which in turn induces DNA damage and upregulates DNA damage response genes. In this context, apoptotic death induced by a second mitochondria-derived activator of caspases (SMAC) mimetic is potentiated by mitofusin inhibition. These data provide mechanistic insights into the function and regulation of mitofusins as well as small molecules to pharmacologically target mitofusins.

DOI: https://doi.org/10.1038/s41467-022-31324-1
Sci Rep. 2022 Jul 07. 12(1): 11533

Spautin-1 inhibits mitochondrial complex I and leads to suppression of the unfolded protein response and cell survival during glucose starvation.

Kazuhiro Kunimasa, Chika Ikeda-Ishikawa, Yuri Tani, Satomi Tsukahara, Junko Sakurai, Yuka Okamoto, Masaru Koido, Shingo Dan, Akihiro Tomida.

The unfolded protein response (UPR) is an adaptive stress response pathway that is essential for cancer cell survival under endoplasmic reticulum stress such as during glucose starvation. In this study, we identified spautin-1, an autophagy inhibitor that suppresses ubiquitin-specific peptidase 10 (USP10) and USP13, as a novel UPR inhibitor under glucose starvation conditions. Spautin-1 prevented the induction of UPR-associated proteins, including glucose-regulated protein 78, activating transcription factor 4, and a splicing variant of x-box-binding protein-1, and showed preferential cytotoxicity in glucose-starved cancer cells. However, USP10 and USP13 silencing and treatment with other autophagy inhibitors failed to result in UPR inhibition and preferential cytotoxicity during glucose starvation. Using transcriptome and chemosensitivity-based COMPARE analyses, we identified a similarity between spautin-1 and mitochondrial complex I inhibitors and found that spautin-1 suppressed the activity of complex I extracted from isolated mitochondria. Our results indicated that spautin-1 may represent an attractive mitochondria-targeted seed compound that inhibits the UPR and cancer cell survival during glucose starvation.

DOI: https://doi.org/10.1038/s41598-022-15673-x
Biochem Biophys Res Commun. 2022 Jun 28. pii: S0006-291X(22)00952-4. [Epub ahead of print]621 1-7

Mitochondrial GCN5L1 regulates cytosolic redox state and hepatic gluconeogenesis via glycerol phosphate shuttle GPD2.

Jiahui Meng, Chunyu Zhang, Danni Wang, Lu Zhu, Lingdi Wang.

  Hepatic gluconeogenesis is crucial for maintaining blood glucose during starvation, and a major contributor for hyperglycemia. Cellular redox state is related to mitochondrial biology and regulates conversion of specific metabolites to glucose. General control of amino acid synthesis 5 (GCN5) like-1 (GCN5L1) is a mitochondria-enriched protein which modulates glucose and amino acid metabolism. Here we show a new regulatory mode of GCN5L1 on gluconeogenesis using lactate and glycerol. We observed GCN5L1 deletion dramatically inhibited glucose production derived from glycerol and lactate, due to increased cytosolic redox state. The underlying mechanism is that GCN5L1 directly binds to the key component of mitochondrial shuttle glycerol phosphate dehydrogenase 2 (GPD2) and modulates its activity. These results have significant implications for understanding the physiological role and regulatory mechanism of mitochondrial shuttle in diabetes development and provide a novel therapeutic potential for diabetes.

Keywords:  Cytosolic redox state; GCN5L1; Gluconeogenesis; Glycerol-3-phosphate dehydrogenase 2; Mitochondrial redox state

DOI:  https://doi.org/10.1016/j.bbrc.2022.06.092
Cell Stem Cell. 2022 Jul 07. pii: S1934-5909(22)00253-3. [Epub ahead of print]29(7): 1119-1134.e7

Amino acid catabolism regulates hematopoietic stem cell proteostasis via a GCN2-eIF2α axis.

Changzheng Li, Binghuo Wu, Yishan Li, Jie Chen, Zhitao Ye, Xiaobin Tian, Jin Wang, Xi Xu, Shuai Pan, Yucan Zheng, Xiongwei Cai, Linjia Jiang, Meng Zhao.

  Hematopoietic stem cells (HSCs) adapt their metabolism to maintenance and proliferation; however, the mechanism remains incompletely understood. Here, we demonstrated that homeostatic HSCs exhibited high amino acid (AA) catabolism to reduce cellular AA levels, which activated the GCN2-eIF2α axis, a protein synthesis inhibitory checkpoint to restrain protein synthesis for maintenance. Furthermore, upon proliferation conditions, HSCs enhanced mitochondrial oxidative phosphorylation (OXPHOS) for higher energy production but decreased AA catabolism to accumulate cellular AAs, which inactivated the GCN2-eIF2α axis to increase protein synthesis and coupled with proteotoxic stress. Importantly, GCN2 deletion impaired HSC function in repopulation and regeneration. Mechanistically, GCN2 maintained proteostasis and inhibited Src-mediated AKT activation to repress mitochondrial OXPHOS in HSCs. Moreover, the glycolytic metabolite, NAD+ precursor nicotinamide riboside (NR), accelerated AA catabolism to activate GCN2 and sustain the long-term function of HSCs. Overall, our study uncovered direct links between metabolic alterations and translation control in HSCs during homeostasis and proliferation.

Keywords:  GCN2; amino acid; hematopoietic stem cells; metabolism; nicotinamide riboside; oxidative phosphorylation; protein translation; proteostasis

DOI:  https://doi.org/10.1016/j.stem.2022.06.004
iScience. 2022 Jul 15. 25(7): 104582

Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation.

Takeshi Tokuyama, Hideki Uosaki, Ayumu Sugiura, Gen Nishitai, Keisuke Takeda, Shun Nagashima, Isshin Shiiba, Naoki Ito, Taku Amo, Satoshi Mohri, Akiyuki Nishimura, Motohiro Nishida, Ayumu Konno, Hirokazu Hirai, Satoshi Ishido, Takahiro Yoshizawa, Takayuki Shindo, Shingo Takada, Shintaro Kinugawa, Ryoko Inatome, Shigeru Yanagi.

  Abnormal mitochondrial fragmentation by dynamin-related protein1 (Drp1) is associated with the progression of aging-associated heart diseases, including heart failure and myocardial infarction (MI). Here, we report a protective role of outer mitochondrial membrane (OMM)-localized E3 ubiquitin ligase MITOL/MARCH5 against cardiac senescence and MI, partly through Drp1 clearance by OMM-associated degradation (OMMAD). Persistent Drp1 accumulation in cardiomyocyte-specific MITOL conditional-knockout mice induced mitochondrial fragmentation and dysfunction, including reduced ATP production and increased ROS generation, ultimately leading to myocardial senescence and chronic heart failure. Furthermore, ischemic stress-induced acute downregulation of MITOL, which permitted mitochondrial accumulation of Drp1, resulted in mitochondrial fragmentation. Adeno-associated virus-mediated delivery of the MITOL gene to cardiomyocytes ameliorated cardiac dysfunction induced by MI. Our findings suggest that OMMAD activation by MITOL can be a therapeutic target for aging-associated heart diseases, including heart failure and MI.

Keywords:  Cellular physiology; Developmental biology; Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2022.104582
J Biol Chem. 2022 Jun 29. pii: S0021-9258(22)00656-1. [Epub ahead of print] 102214

Overexpression of MRX9 impairs processing of RNAs encoding mitochondrial oxidative phosphorylation factors COB and COX1 in yeast.

Jhulia Almeida Clarck Chagas, Maria Antônia Kfouri Martins Soares, Leticia Veloso Ribeiro Franco, Mário H Barros.

  Mitochondrial translation is a highly regulated process, and newly synthesized mitochondrial products must first associate with several nuclear-encoded auxiliary factors to form oxidative phosphorylation complexes. The output of mitochondrial products should therefore be in stoichiometric equilibrium with the nuclear-encoded products to prevent unnecessary energy expense or the accumulation of pro-oxidant assembly modules. In the mtDNA of Saccharomyces cerevisiae, COX1 encodes subunit 1 of the cytochrome c oxidase, and COB the central core of the cytochrome bc1 electron transfer complex; however, factors regulating the expression of these mitochondrial products are not well described. In this study, we identified Mrx9p as a new factor that controls COX1 and COB expression. We isolated MRX9 in a screen for mitochondrial factors that cause poor accumulation of newly synthesized Cox1p and compromised transition to the respiratory metabolism. Northern analyses indicated lower levels of COX1 and COB mature mRNAs accompanied by an accumulation of unprocessed transcripts in the presence of excess Mrx9p. Furthermore, in a strain devoid of mitochondrial introns, MRX9 overexpression did not affect COX1 and COB translation or respiratory adaptation, implying Mrx9p regulates processing of COX1 and COB RNAs. In addition, we found Mrx9p was localized in the mitochondrial inner membrane, facing the matrix, as a portion of it co-sedimented with mitoribosome subunits and its removal or overexpression altered Mss51p sedimentation. Finally, we showed accumulation of newly synthesized Cox1p in the absence of Mrx9p was diminished in cox14 null mutants. Taken together, these data indicate a regulatory role of Mrx9p in COX1 RNA processing.

Keywords:  Saccharomyces cerevisiae; intron processing; mitochondrial translation

DOI:  https://doi.org/10.1016/j.jbc.2022.102214
Biogerontology. 2022 Jul 04.

Mitochondria-targeted senotherapeutic interventions.

Mehmet Can Atayik, Ufuk Çakatay.

  Healthy aging is the art of balancing a delicate scale. On one side of the scale, there are the factors that make life difficult with aging, and on the other side are the products of human effort against these factors. The most important factors that make the life difficult with aging are age-related disorders. Developing senotherapeutic strategies may bring effective solutions for the sufferers of age-related disorders. Mitochondrial dysfunction comes first in elucidating the pathogenesis of age-related disorders and presenting appropriate treatment options. Although it has been widely accepted that mitochondrial dysfunction is a common characteristic of cellular senescence, it still remains unclear why dysfunctional mitochondria occupy a central position in the development senescence-associated secretory phenotype (SASP) related to age-related disorders. Mitochondrial dysfunction and SASP-related disease progression are closely interlinked to weaken immunity which is a common phenomenon in aging. A group of substances known as senotherapeutics targeted to senescent cells can be classified into two main groups: senolytics (kill senescent cells) and senomorphics/senostatics (suppress their SASP secretions) in order to extend health lifespan and potentially lifespan. As mitochondria are also closely related to the survival of senescent cells, using either mitochondria-targeted senolytic or redox modulator senomorphic strategies may help us to solve the complex problems with the detrimental consequences of cellular senescence. Killing of senescent cells and/or ameliorate their SASP-related negative effects are currently considered to be effective mitochondria-directed gerotherapeutic approaches for fighting against age-related disorders.

Keywords:  Aging; Mitochondria; Senescence; Senotherapeutics

DOI:  https://doi.org/10.1007/s10522-022-09973-y
Med Microbiol Immunol. 2022 Jul 05.

Mitochondria: intracellular sentinels of infections.

Dominik Brokatzky, Georg Häcker.

  Structure and integrity of the mitochondrial network play important roles in many cellular processes. Loss of integrity can lead to the activation of a variety of signalling pathways and affect the cell's response to infections. The activation of such mitochondria-mediated cellular responses has implications for infection recognition, signal transduction and pathogen control. Although we have a basic understanding of mitochondrial factors such as mitochondrial DNA or RNA that may be involved in processes like pro-inflammatory signalling, the diverse roles of mitochondria in host defence remain unclear. Here we will first summarise the functions of mitochondria in the host cell and provide an overview of the major known mitochondrial stress responses. We will then present recent studies that have contributed to the understanding of the role of mitochondria in infectious diseases and highlight a number of recently investigated models of bacterial and viral infections.

Keywords:  Infection; Inflammation; Innate immunity; Metabolism; Mitochondria; Stress responses

DOI:  https://doi.org/10.1007/s00430-022-00742-9
Nat Rev Mol Cell Biol. 2022 Jul 08.

Mechanisms of mitochondrial respiratory adaptation.

Christopher F Bennett, Pedro Latorre-Muro, Pere Puigserver.

Mitochondrial energetic adaptations encompass a plethora of conserved processes that maintain cell and organismal fitness and survival in the changing environment by adjusting the respiratory capacity of mitochondria. These mitochondrial responses are governed by general principles of regulatory biology exemplified by changes in gene expression, protein translation, protein complex formation, transmembrane transport, enzymatic activities and metabolite levels. These changes can promote mitochondrial biogenesis and membrane dynamics that in turn support mitochondrial respiration. The main regulatory components of mitochondrial energetic adaptation include: the transcription coactivator peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC1α) and associated transcription factors; mTOR and endoplasmic reticulum stress signalling; TOM70-dependent mitochondrial protein import; the cristae remodelling factors, including mitochondrial contact site and cristae organizing system (MICOS) and OPA1; lipid remodelling; and the assembly and metabolite-dependent regulation of respiratory complexes. These adaptive molecular and structural mechanisms increase respiration to maintain basic processes specific to cell types and tissues. Failure to execute these regulatory responses causes cell damage and inflammation or senescence, compromising cell survival and the ability to adapt to energetically demanding conditions. Thus, mitochondrial adaptive cellular processes are important for physiological responses, including to nutrient availability, temperature and physical activity, and their failure leads to diseases associated with mitochondrial dysfunction such as metabolic and age-associated diseases and cancer.

DOI: https://doi.org/10.1038/s41580-022-00506-6
Biochim Biophys Acta Bioenerg. 2022 Jun 30. pii: S0005-2728(22)00057-3. [Epub ahead of print]1863(7): 148588

Mitochondria - Nucleus communication in neurodegenerative disease. Who talks first, who talks louder?

Diana Iulia Savu, Nicoleta Moisoi.

  Mitochondria - nuclear coadaptation has been central to eukaryotic evolution. The dynamic dialogue between the two compartments within the context of multiorganellar interactions is critical for maintaining cellular homeostasis and directing the balance survival-death in case of cellular stress. The conceptualisation of mitochondria - nucleus communication has so far been focused on the communication from the mitochondria under stress to the nucleus and the consequent signalling responses, as well as from the nucleus to mitochondria in the context of DNA damage and repair. During ageing processes this dialogue may be better viewed as an integrated bidirectional 'talk' with feedback loops that expand beyond these two organelles depending on physiological cues. Here we explore the current views on mitochondria - nucleus dialogue and its role in maintaining cellular health with a focus on brain cells and neurodegenerative disease. Thus, we detail the transcriptional responses initiated by mitochondrial dysfunction in order to protect itself and the general cellular homeostasis. Additionally, we are reviewing the knowledge of the stress pathways initiated by DNA damage which affect mitochondria homeostasis and we add the information provided by the study of combined mitochondrial and genotoxic damage. Finally, we reflect on how each organelle may take the lead in this dialogue in an ageing context where both compartments undergo accumulation of stress and damage and where, perhaps, even the communications' mechanisms may suffer interruptions.

Keywords:  DNA damage; Mitochondria nucleus communication; Mitochondrial damage; Neurodegeneration; Stress signalling

DOI:  https://doi.org/10.1016/j.bbabio.2022.148588
Life Sci. 2022 Jul 01. pii: S0024-3205(22)00453-2. [Epub ahead of print] 120753

Emerging role of mitochondrial DAMPs, aberrant mitochondrial dynamics and anomalous mitophagy in gut mucosal pathogenesis.

Somnath Mazumder, Samik Bindu, Rudranil De, Subhashis Debsharma, Saikat Pramanik, Uday Bandyopadhyay.

  Gastroduodenal inflammation and ulcerative injuries are increasing due to expanding socio-economic stress, unhealthy food habits-lifestyle, smoking, alcoholism and usage of medicines like non-steroidal anti-inflammatory drugs. In fact, gastrointestinal (GI) complications, associated with the prevailing COVID-19 pandemic, further, poses a challenge to global healthcare towards safeguarding the GI tract. Emerging evidences have discretely identified mitochondrial dysfunctions as common etiological denominators in diseases. However, it is worth realizing that mitochondrial dysfunctions are not just consequences of diseases. Rather, damaged mitochondria severely aggravate the pathogenesis thereby qualifying as perpetrable factors worth of prophylactic and therapeutic targeting. Oxidative and nitrosative stress due to endogenous and exogenous stimuli triggers mitochondrial injury causing production of mitochondrial damage associated molecular patterns (mtDAMPs), which, in a feed-forward loop, inflicts inflammatory tissue damage. Mitochondrial structural dynamics and mitophagy are crucial quality control parameters determining the extent of mitopathology and disease outcomes. Interestingly, apart from endogenous factors, mitochondria also crosstalk and in turn get detrimentally affected by gut pathobionts colonized during luminal dysbiosis. Although mitopathology is documented in various pre-clinical/clinical studies, a comprehensive account appreciating the mitochondrial basis of GI mucosal pathologies is largely lacking. Here we critically discuss the molecular events impinging on mitochondria along with the interplay of mitochondria-derived factors in fueling mucosal pathogenesis. We specifically emphasize on the potential role of aberrant mitochondrial dynamics, anomalous mitophagy, mitochondrial lipoxidation and ferroptosis as emerging regulators of GI mucosal pathogenesis. We finally discuss about the prospect of mitochondrial targeting for next-generation drug discovery against GI disorders.

Keywords:  COVID-19; Inflammation; Inflammatory bowel disease; Mitochondria targeted antioxidants; Mitochondrial oxidative stress; Peptic ulcer

DOI:  https://doi.org/10.1016/j.lfs.2022.120753
Annu Rev Cell Dev Biol. 2022 Jul 08.

Senescence: An Identity Crisis Originating from Deep Within the Nucleus.

Ioana Olan, Masashi Narita.

Cellular senescence is implicated in a wide range of physiological and pathological conditions throughout an organism's entire lifetime. In particular, it has become evident that senescence plays a causative role in aging and age-associated disorders. This is not due simply to the loss of function of senescent cells. Instead, the substantial alterations of the cellular activities of senescent cells, especially the array of secretory factors, impacts the surrounding tissues or even entire organisms. Such non-cell-autonomous functionality is largely coordinated by tissue-specific genes, constituting a cell fate-determining state. Senescence can be viewed as a gain-of-function phenotype or a process of cell identity shift. Cellular functionality or lineage-specific gene expression is tightly linked to the cell type-specific epigenetic landscape, reinforcing the heterogeneity of senescence across cell types. Here, we aim to define the senescence cellular functionality and epigenetic features that may contribute to the gain-of-function phenotype. Expected final online publication date for the Annual Review of Cell and Developmental Biology Volume 38 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-cellbio-120420-013537
Annu Rev Cell Dev Biol. 2022 Jul 08.

Mitochondria as Cellular and Organismal Signaling Hubs.

Koning Shen, Corinne L Pender, Raz Bar-Ziv, Hanlin Zhang, Kevin Wickham, Elizabeth Willey, Jenni Durieux, Qazi Ahmad, Andrew Dillin.

Mitochondria are traditionally known as the powerhouse of the cell, but their functions extend far beyond energy production. They are vital in cellular and organismal pathways that direct metabolism, stress responses, immunity, and cellular fate. To accomplish these tasks, mitochondria have established networks of both intra- and extracellular communication. Intracellularly, these communication routes comprise direct contacts between mitochondria and other subcellular components as well as indirect vesicle transport of ions, metabolites, and other intracellular messengers. Extracellularly, mitochondria can induce stress responses or other cellular changes that secrete mitochondrial cytokine (mitokine) factors that can travel between tissues as well as respond to immune challenges from extracellular sources. Here we provide a current perspective on the major routes of communication for mitochondrial signaling, including their mechanisms and physiological impact. We also review the major diseases and age-related disorders associated with defects in these signaling pathways. An understanding of how mitochondrial signaling controls cellular homeostasis will bring greater insight into how dysfunctional mitochondria affect health in disease and aging. Expected final online publication date for the Annual Review of Cell and Developmental Biology Volume 38 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-cellbio-120420-015303
J Clin Invest. 2022 Jul 05. pii: e151540. [Epub ahead of print]

Tetracycline-induced mitohormesis mediates disease tolerance against influenza.

Adrienne Mottis, Terytty Y Li, Gaby El Alam, Alexis Rapin, Elena Katsyuba, David Liaskos, Davide D'Amico, Nicola L Harris, Mark C Grier, Laurent Mouchiroud, Mark L Nelson, Johan Auwerx.

  Mitohormesis defines the increase in fitness mediated by adaptive responses to mild mitochondrial stress. Tetracyclines inhibit not only bacterial but also mitochondrial translation, thus imposing a low level of mitochondrial stress to eukaryotic cells. We demonstrate in cell and germ-free mouse models, that tetracyclines induce a mild adaptive mitochondrial stress response (MSR), involving both the ATF4-mediated integrative stress response and type I interferon (IFN) signaling. To overcome the interferences of tetracyclines with the host microbiome, we identify tetracycline derivatives that have minimal antimicrobial activity, yet retain full capacity to induce the MSR, such as the lead compound, 9-tert-butyldoxycycline (9-TB). The MSR induced by Doxycycline (Dox) and 9-TB improves survival and disease tolerance against lethal influenza virus (IFV) infection when given preventively. 9-TB, unlike Dox, did not affect the gut microbiome and showed also encouraging results against IFV when given in a therapeutic setting. Tolerance to IFV infection is associated with the induction of genes involved in lung epithelial cell and cilia function, and with down-regulation of inflammatory and immune gene sets in lungs, liver, and kidneys. Mitohormesis induced by non-antimicrobial tetracyclines and the ensuing IFN response may dampen excessive inflammation and tissue damage during viral infections, opening innovative therapeutic avenues.

Keywords:  Drug therapy; Infectious disease; Influenza; Mitochondria

DOI:  https://doi.org/10.1172/JCI151540
Cells. 2022 Jun 30. pii: 2079. [Epub ahead of print]11(13):

Mitoribosomal Deregulation Drives Senescence via TPP1-Mediated Telomere Deprotection.

Seongki Min, So Mee Kwon, Jiwon Hong, Young-Kyoung Lee, Tae Jun Park, Su Bin Lim, Gyesoon Yoon.

  While mitochondrial bioenergetic deregulation has long been implicated in cellular senescence, its mechanistic involvement remains unclear. By leveraging diverse mitochondria-related gene expression profiles derived from two different cellular senescence models of human diploid fibroblasts, we found that the expression of mitoribosomal proteins (MRPs) was generally decreased during the early-to-middle transition prior to the exhibition of noticeable SA-β-gal activity. Suppressed expression patterns of the identified senescence-associated MRP signatures (SA-MRPs) were validated in aged human cells and rat and mouse skin tissues and in aging mouse fibroblasts at single-cell resolution. TIN2- and POT1-interaction protein (TPP1) was concurrently suppressed, which induced senescence, accompanied by telomere DNA damage. Lastly, we show that SA-MRP deregulation could be a potential upstream regulator of TPP1 suppression. Our results indicate that mitoribosomal deregulation could represent an early event initiating mitochondrial dysfunction and serve as a primary driver of cellular senescence and an upstream regulator of shelterin-mediated telomere deprotection.

Keywords:  mitoribosome; replicative senescence; shelterin; telomere maintenance

DOI:  https://doi.org/10.3390/cells11132079
Biochim Biophys Acta Mol Basis Dis. 2022 Jul 02. pii: S0925-4439(22)00152-1. [Epub ahead of print] 166481

Uncovering the source of mitochondrial superoxide in pro-inflammatory macrophages: Insights from immunometabolism.

Alva M Casey, Michael P Murphy.

  Mitochondrial-derived reactive oxygen species are important as antimicrobial agents and redox signals in pro-inflammatory macrophages. Macrophages produce superoxide in response to the TLR4 ligand LPS. However, the mechanism of LPS-induced superoxide generation is not fully understood. Superoxide is produced at complex I and complex III of the electron transport chain. Production of superoxide at either of these sites is highly dependent on the metabolic state of the cell which is dramatically altered by TLR4-induced metabolic reprogramming. This review will outline how metabolism impacts superoxide production in LPS-activated macrophages downstream of TLR4 signalling and address outstanding questions in this field.

Keywords:  Complex I; Macrophages; Metabolism; Mitochondria; Reverse electron transport; Superoxide

DOI:  https://doi.org/10.1016/j.bbadis.2022.166481