bims-minimp 2021-10-10 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2021–10–10
thirty-two papers selected by
Hanna Salmonowicz, International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

Protective mitochondrial fission induced by stress-responsive protein GJA1-20k.
Mild mitochondrial impairment enhances inn3ate immunity and longevity through ATFS-1 and p38 signaling.
TFAM knockdown-triggered mtDNA-nucleoid aggregation and a decrease in mtDNA copy number induce the reorganization of nucleoid populations and mitochondria-associated ER-membrane contacts.
Ubiquitination of ATF6 by disease-associated RNF186 promotes the innate receptor-induced unfolded protein response.
Sirt1 promotes tissue regeneration in zebrafish through regulating the mitochondrial unfolded protein response.
Beyond Base Excision Repair: An evolving picture of mitochondrial DNA repair.
The assembly, regulation and function of the mitochondrial respiratory chain.
A simple mechanistic explanation for Barth syndrome and cardiolipin remodeling.
Relieving Cellular Energy Stress in Aging, Neurodegenerative, and Metabolic Diseases, SIRT1 as a Therapeutic and Promising Node.
Yes, MAM!
Mitofusin 2: the missing link between mtDNA maintenance defects and neurotransmitter disorders.
Visualizing formation of the active site in the mitochondrial ribosome.
cGAS-STING-mediated sensing pathways in DNA and RNA virus infections: crosstalk with other sensing pathways.
A replication-linked mutational gradient drives somatic mutation accumulation and influences germline polymorphisms and genome composition in mitochondrial DNA.
Managing risky assets - mitophagy in vivo.
FTSH4 and OMA1 mitochondrial proteases reduce moderate heat stress-induced protein aggregation.
Canary in a coal mine: collided ribosomes as sensors of cellular conditions.
Natural tetramic acids elicit multiple inhibitory actions against mitochondrial machineries presiding over oxidative phosphorylation.
Nucleus-mitochondria positive feedback loop formed by ERK5 S496 phosphorylation-mediated poly (ADP-ribose) polymerase activation provokes persistent pro-inflammatory senescent phenotype and accelerates coronary atherosclerosis after chemo-radiation.
The multifaceted ATPase inhibitory factor 1 (IF1) in energy metabolism reprogramming and mitochondrial dysfunction: a new player in age-associated disorders?
Targeting senescent immune cells to rejuvenate the aging skeleton.
Respiratory Complex I dysfunction in cancer: from a maze of cellular adaptive responses to potential therapeutic strategies.
Seeking protective mitochondria.
PINK1 drives production of mtDNA-containing extracellular vesicles to promote invasiveness.
Modulation of SF3B1 in the pre-mRNA spliceosome induces a RIG-I-dependent type I IFN response.
Mitonuclear Interactions Produce Diverging Responses to Mild Stress in Drosophila Larvae.
Correlated electric field modulation of electron transfer parameters and the access to alternative conformations of multifunctional cytochrome c.
If you can't freeze it, chew it: roles of mitochondrial proteases in plant heat stress protection.
ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis.
The Contribution of Physiological and Accelerated Aging to Cancer Progression Through Senescence-Induced Inflammation.
Reversible amyloids of pyruvate kinase couple cell metabolism and stress granule disassembly.
Modulation of fracture healing by the transient accumulation of senescent cells.

Elife. 2021 10 05. pii: e69207. [Epub ahead of print]10

Protective mitochondrial fission induced by stress-responsive protein GJA1-20k.

Daisuke Shimura, Esther Nuebel, Rachel Baum, Steven E Valdez, Shaohua Xiao, Junco S Warren, Joseph A Palatinus, TingTing Hong, Jared Rutter, Robin M Shaw.

  The Connexin43 gap junction gene GJA1 has one coding exon, but its mRNA undergoes internal translation to generate N-terminal truncated isoforms of Connexin43 with the predominant isoform being only 20 kDa in size (GJA1-20k). Endogenous GJA1-20k protein is not membrane bound and has been found to increase in response to ischemic stress, localize to mitochondria, and mimic ischemic preconditioning protection in the heart. However, it is not known how GJA1-20k benefits mitochondria to provide this protection. Here, using human cells and mice, we identify that GJA1-20k polymerizes actin around mitochondria which induces focal constriction sites. Mitochondrial fission events occur within about 45 s of GJA1-20k recruitment of actin. Interestingly, GJA1-20k mediated fission is independent of canonical Dynamin-Related Protein 1 (DRP1). We find that GJA1-20k-induced smaller mitochondria have decreased reactive oxygen species (ROS) generation and, in hearts, provide potent protection against ischemia-reperfusion injury. The results indicate that stress responsive internally translated GJA1-20k stabilizes polymerized actin filaments to stimulate non-canonical mitochondrial fission which limits ischemic-reperfusion induced myocardial infarction.

Keywords:  GJA1-20k; actin dynamics; cell biology; human; ischemia/reperfusion; mitochondria; mitochondria dynamics; mouse; organ protection

DOI:  https://doi.org/10.7554/eLife.69207
EMBO Rep. 2021 Oct 07. e52964

Mild mitochondrial impairment enhances inn3ate immunity and longevity through ATFS-1 and p38 signaling.

Juliane C Campos, Ziyun Wu, Paige D Rudich, Sonja K Soo, Meeta Mistry, Julio Cb Ferreira, T Keith Blackwell, Jeremy M Van Raamsdonk.

  While mitochondrial function is essential for life in all multicellular organisms, a mild impairment of mitochondrial function can extend longevity in model organisms. By understanding the molecular mechanisms involved, these pathways might be targeted to promote healthy aging. In studying two long-lived mitochondrial mutants in C. elegans, we found that disrupting subunits of the mitochondrial electron transport chain results in upregulation of genes involved in innate immunity, which is driven by the mitochondrial unfolded protein response (mitoUPR) but also dependent on the canonical p38-mediated innate immune signaling pathway. Both of these pathways are required for the increased resistance to bacterial pathogens and extended longevity of the long-lived mitochondrial mutants, as is the FOXO transcription factor DAF-16. This work demonstrates that both the p38-mediated innate immune signaling pathway and the mitoUPR act in concert on the same innate immunity genes to promote pathogen resistance and longevity and that input from the mitochondria can extend longevity by signaling through these pathways. This indicates that multiple evolutionarily conserved genetic pathways controlling innate immunity also function to modulate lifespan.

Keywords:   C. elegans ; aging; innate immunity; mitochondria; mitochondrial unfolded protein response

DOI:  https://doi.org/10.15252/embr.202152964
Biochem Biophys Rep. 2021 Dec;28 101142

TFAM knockdown-triggered mtDNA-nucleoid aggregation and a decrease in mtDNA copy number induce the reorganization of nucleoid populations and mitochondria-associated ER-membrane contacts.

Koit Aasumets, Yuliya Basikhina, Jaakko L Pohjoismäki, Steffi Goffart, Joachim Gerhold.

  The correct organization of mitochondrial DNA (mtDNA) in nucleoids and the contacts of mitochondria with the ER play an important role in maintaining the mitochondrial genome distribution within the cell. Mitochondria-associated ER membranes (MAMs) consist of interacting proteins and lipids located in the outer mitochondrial membrane and ER membrane, forming a platform for the mitochondrial inner membrane-associated genome replication factory as well as connecting the nucleoids with the mitochondrial division machinery. We show here that knockdown of a core component of mitochondrial nucleoids, TFAM, causes changes in the mitochondrial nucleoid populations, which subsequently impact ER-mitochondria membrane contacts. Knockdown of TFAM causes a significant decrease in the copy number of mtDNA as well as aggregation of mtDNA nucleoids. At the same time, it causes significant upregulation of the replicative TWNK helicase in the membrane-associated nucleoid fraction. This is accompanied by a transient elevation of MAM proteins, indicating a rearrangement of the linkage between ER and mitochondria triggered by changes in mitochondrial nucleoids. Reciprocal knockdown of the mitochondrial replicative helicase TWNK causes a decrease in mtDNA copy number and modifies mtDNA membrane association, however, it does not cause nucleoid aggregation and considerable alterations of MAM proteins in the membrane-associated fraction. Our explanation is that the aggregation of mitochondrial nucleoids resulting from TFAM knockdown triggers a compensatory mechanism involving the reorganization of both mitochondrial nucleoids and MAM. These results could provide an important insight into pathological conditions associated with impaired nucleoid organization or defects of mtDNA distribution.

Keywords:  Mitochondrial DNA; Mitochondrial transcription factor A (TFAM); Nucleoids; Organellar membranes; TWNK helicase

DOI:  https://doi.org/10.1016/j.bbrep.2021.101142
J Clin Invest. 2021 Sep 01. pii: e145472. [Epub ahead of print]131(17):

Ubiquitination of ATF6 by disease-associated RNF186 promotes the innate receptor-induced unfolded protein response.

Kishu Ranjan, Matija Hedl, Saloni Sinha, Xuchen Zhang, Clara Abraham.

  Properly balancing microbial responses by the innate immune system through pattern recognition receptors (PRRs) is critical for intestinal immune homeostasis. Ring finger protein 186 (RNF186) genetic variants are associated with inflammatory bowel disease (IBD). However, functions for the E3 ubiquitin ligase RNF186 are incompletely defined. We found that upon stimulation of the PRR nucleotide-binding oligomerization domain containing 2 (NOD2) in human macrophages, RNF186 localized to the ER, formed a complex with ER stress sensors, ubiquitinated the ER stress sensor activating transcription factor 6 (ATF6), and promoted the unfolded protein response (UPR). These events, in turn, led to downstream signaling, cytokine secretion, and antimicrobial pathway induction. Importantly, RNF186-mediated ubiquitination of K152 on ATF6 was required for these outcomes, highlighting a key role for ATF6 ubiquitination in PRR-initiated functions. Human macrophages transfected with the rare RNF186-A64T IBD risk variant and macrophages from common rs6426833 RNF186 IBD risk carriers demonstrated reduced NOD2-induced outcomes, which were restored by rescuing UPR signaling. Mice deficient in RNF186 or ATF6 demonstrated a reduced UPR in colonic tissues, increased weight loss, and less effective clearance of bacteria with dextran sodium sulfate-induced injury and upon oral challenge with Salmonella Typhimurium. Therefore, we identified that RNF186 was required for PRR-induced, UPR-associated signaling leading to key macrophage functions; defined that RNF186-mediated ubiquitination of ATF6 was essential for these functions; and elucidated how RNF186 IBD risk variants modulated these outcomes.

Keywords:  Immunology; Innate immunity; Macrophages

DOI:  https://doi.org/10.1172/JCI145472
iScience. 2021 Oct 22. 24(10): 103118

Sirt1 promotes tissue regeneration in zebrafish through regulating the mitochondrial unfolded protein response.

Yi-Fan Lin, Jessica Sam, Todd Evans.

  The mitochondrial unfolded protein response (UPRmt) is an organellar stress signaling pathway that functions to detect and restore disruption of mitochondrial proteostasis. The UPRmt is involved in a wide range of physiological and disease conditions, including aging, stem cell maintenance, innate immunity, neurodegeneration, and cancer. Here we report that the UPRmt is integral to zebrafish fin regeneration. Taking advantage of a novel zebrafish UPRmt reporter, we observed that UPRmt activation occurs in regenerating fin tissue shortly after injury. Through chemical and genetic approaches, we discovered that the Sirt1-UPRmt pathway, best known for its role in promoting lifespan extension, is crucial for fin regeneration. The metabolism of NAD+ is an important contributor to Sirt1 activity in this context. We propose that Sirt1 activation induces mitochondrial biogenesis in injured fin tissue, which leads to UPRmt activation and promotes tissue regeneration.

Keywords:  Cell biology; Developmental biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2021.103118
Biosci Rep. 2021 Oct 05. pii: BSR20211320. [Epub ahead of print]

Beyond Base Excision Repair: An evolving picture of mitochondrial DNA repair.

Kathrin Allkanjari, Robert A Baldock.

  Mitochondria are highly specialised organelles required for cellular processes including ATP-production through cellular respiration and controlling apoptosis. Mitochondria contain their own DNA genome which encodes both protein and RNA required for cellular respiration. Each cell may contain hundreds to thousands of copies of the mitochondrial genome, which is essential for normal cellular function - deviation of mitochondrial DNA (mtDNA) copy number is associated with cellular aging and disease. Furthermore, mtDNA lesions can arise from both endogenous or exogenous sources and must either be tolerated or corrected to preserve mitochondrial function. Importantly, replication of damaged mtDNA can lead to stalling and introduction of mutations or genetic loss, mitochondria have adapted mechanisms to repair damaged DNA. These mechanisms rely on nuclear encoded DNA repair proteins that are translocated into the mitochondria. Despite the presence of many known nuclear DNA repair proteins being found in the mitochondrial proteome, it remains to be established which DNA repair mechanisms are functional in mammalian mitochondria. Here, we summarise the existing and emerging research, alongside examining proteomic evidence, demonstrating that mtDNA damage can be repaired using Base Excision Repair (BER), Homologous Recombination (HR) and Microhomology-mediated End Joining (MMEJ). Critically, these repair mechanisms do not operate in isolation and evidence for interplay between pathways and repair associated with replication is discussed. Importantly, characterising non-canonical functions of key proteins and understanding the bespoke pathways used to tolerate, repair or bypass DNA damage will be fundamental in fully understanding the causes of mitochondrial genome mutations and mitochondrial dysfunction.

Keywords:  DNA replication and recombination; DNA synthesis and repair; genome integrity; mtDNA

DOI:  https://doi.org/10.1042/BSR20211320
Nat Rev Mol Cell Biol. 2021 Oct 07.

The assembly, regulation and function of the mitochondrial respiratory chain.

Irene Vercellino, Leonid A Sazanov.

The mitochondrial oxidative phosphorylation system is central to cellular metabolism. It comprises five enzymatic complexes and two mobile electron carriers that work in a mitochondrial respiratory chain. By coupling the oxidation of reducing equivalents coming into mitochondria to the generation and subsequent dissipation of a proton gradient across the inner mitochondrial membrane, this electron transport chain drives the production of ATP, which is then used as a primary energy carrier in virtually all cellular processes. Minimal perturbations of the respiratory chain activity are linked to diseases; therefore, it is necessary to understand how these complexes are assembled and regulated and how they function. In this Review, we outline the latest assembly models for each individual complex, and we also highlight the recent discoveries indicating that the formation of larger assemblies, known as respiratory supercomplexes, originates from the association of the intermediates of individual complexes. We then discuss how recent cryo-electron microscopy structures have been key to answering open questions on the function of the electron transport chain in mitochondrial respiration and how supercomplexes and other factors, including metabolites, can regulate the activity of the single complexes. When relevant, we discuss how these mechanisms contribute to physiology and outline their deregulation in human diseases.

DOI: https://doi.org/10.1038/s41580-021-00415-0
J Inherit Metab Dis. 2021 Oct 05.

A simple mechanistic explanation for Barth syndrome and cardiolipin remodeling.

Yang Xu, Colin K L Phoon, Mindong Ren, Michael Schlame.

Barth syndrome is a multisystem disorder caused by an abnormal metabolism of the mitochondrial lipid cardiolipin. In this review, we discuss physical properties, biosynthesis, membrane assembly, and function of cardiolipin. We hypothesize that cardiolipin reduces packing stress in the inner mitochondrial membrane, which arises as a result of protein crowding. According to this hypothesis, patients with Barth syndrome are unable to meet peak energy demands because they fail to concentrate the proteins of oxidative phosphorylation to a high surface density in the inner mitochondrial membrane. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/jimd.12445
Front Aging Neurosci. 2021 ;13 738686

Relieving Cellular Energy Stress in Aging, Neurodegenerative, and Metabolic Diseases, SIRT1 as a Therapeutic and Promising Node.

Yang Fang, Xifeng Wang, Danying Yang, Yimei Lu, Gen Wei, Wen Yu, Xing Liu, Qingcui Zheng, Jun Ying, Fuzhou Hua.

  The intracellular energy state will alter under the influence of physiological or pathological stimuli. In response to this change, cells usually mobilize various molecules and their mechanisms to promote the stability of the intracellular energy status. Mitochondria are the main source of ATP. Previous studies have found that the function of mitochondria is impaired in aging, neurodegenerative diseases, and metabolic diseases, and the damaged mitochondria bring lower ATP production, which further worsens the progression of the disease. Silent information regulator-1 (SIRT1) is a multipotent molecule that participates in the regulation of important biological processes in cells, including cellular metabolism, cell senescence, and inflammation. In this review, we mainly discuss that promoting the expression and activity of SIRT1 contributes to alleviating the energy stress produced by physiological and pathological conditions. The review also discusses the mechanism of precise regulation of SIRT1 expression and activity in various dimensions. Finally, according to the characteristics of this mechanism in promoting the recovery of mitochondrial function, the relationship between current pharmacological preparations and aging, neurodegenerative diseases, metabolic diseases, and other diseases was analyzed.

Keywords:  AMP-dependent protein kinases; NAD+; SIRT1-activating compounds; age-related diseases; aging; cellular energy stress; silent information regulator-1

DOI:  https://doi.org/10.3389/fnagi.2021.738686
Mol Cell Oncol. 2021 ;8(4): 1919473

Yes, MAM!

Robert E Means, Samuel G Katz.

  Regulation of cell life and death by members of the BCL-2 family of proteins occurs at the mitochondria. Large portions of the mitochondria's outer membrane are found in tight approximation with the endoplasmic reticulum (ER), known as mitochondria-associated membranes (MAMs) or mitochondria-ER contact sites (MERCs). We recently reported that BOK is present within MAMs where it regulates Ca2+ transfer from the ER to the mitochondria, appropriate MAM components and MERC structure, and apoptosis.

Keywords:  BCL-2; BOK; MAM; MERC; apoptosis; calcium

DOI:  https://doi.org/10.1080/23723556.2021.1919473
Mitochondrion. 2021 Sep 29. pii: S1567-7249(21)00137-9. [Epub ahead of print]

Mitofusin 2: the missing link between mtDNA maintenance defects and neurotransmitter disorders.

Giuditta Pellino, Raffaella Faggioli, Anna Galuppi, Alberta Leon, Carlo Fusco, Valeria Tugnoli, Agnese Suppiej.

  Mitofusin (MFN) 2 belongs to the large family of mitochondrial transmembrane GTPases and has a role in dynamic mitochondrial remodeling process governed by fusion and fission. MFN2 pathogenic variants classically cause Charcot-Marie-Tooth disease type 2A (CMT2A), the most common axonal form of CMT, but patients with complex and unusual phenotypes involving the central and peripheral nervous system have been described, with mitochondrial dysfunction proposed as the underlying pathogenic mechanism. Here, we report the first description of a neurochemical pattern of secondary alterations in the metabolism of biogenic amines linked to the de novo presence of the hotspot MFN2 pathogenic variant p.Arg104Trp. The infant presented a very early onset choreic movement disorder associated with severe axial hypotonia and fluctuating dystonia of limbs. The relationship between mitochondrial DNA (mtDNA) maintenance defects and dopaminergic neurotransmitter disorders, governed by MFN2, is discussed.

Keywords:  CSF biogenic amine disorder; Charcot-Marie-Tooth disease; MFN2; mtDNA depletion syndrome

DOI:  https://doi.org/10.1016/j.mito.2021.09.011
Elife. 2021 10 05. pii: e68806. [Epub ahead of print]10

Visualizing formation of the active site in the mitochondrial ribosome.

Viswanathan Chandrasekaran, Nirupa Desai, Nicholas O Burton, Hanting Yang, Jon Price, Eric A Miska, V Ramakrishnan.

  Ribosome assembly is an essential and conserved process that is regulated at each step by specific factors. Using cryo-electron microscopy (cryo-EM), we visualize the formation of the conserved peptidyl transferase center (PTC) of the human mitochondrial ribosome. The conserved GTPase GTPBP7 regulates the correct folding of 16S ribosomal RNA (rRNA) helices and ensures 2'-O-methylation of the PTC base U3039. GTPBP7 binds the RNA methyltransferase NSUN4 and MTERF4, which sequester H68-71 of the 16S rRNA and allow biogenesis factors to access the maturing PTC. Mutations that disrupt binding of their Caenorhabditis elegans orthologs to the large subunit potently activate mitochondrial stress and cause viability, development, and sterility defects. Next-generation RNA sequencing reveals widespread gene expression changes in these mutant animals that are indicative of mitochondrial stress response activation. We also answer the long-standing question of why NSUN4, but not its enzymatic activity, is indispensable for mitochondrial protein synthesis.

Keywords:  C. elegans; RNA modifications; biochemistry; chemical biology; cryo-EM; human; mitochondrial ribosome; molecular biophysics; peptidyl transferase center; structural biology

DOI:  https://doi.org/10.7554/eLife.68806
Arch Virol. 2021 Oct 07.

cGAS-STING-mediated sensing pathways in DNA and RNA virus infections: crosstalk with other sensing pathways.

Saleem Anwar, Khursheed Ul Islam, Md Iqbal Azmi, Jawed Iqbal.

Viruses cause a variety of diseases in humans and other organisms. The most important defense mechanism against viral infections is initiated when the viral genome is sensed by host proteins, and this results in interferon production and pro-inflammatory cytokine responses. The sensing of the viral genome or its replication intermediates within host cells is mediated by cytosolic proteins. For example, cGAS and IFI16 recognize non-self DNA, and RIG-I and MDA5 recognize non-self RNA. Once these sensors are activated, they trigger a cascade of reactions activating downstream molecules, which eventually results in the transcriptional activation of type I and III interferons, which play a critical role in suppressing viral propagation, either by directly limiting their replication or by inducing host cells to inhibit viral protein synthesis. The immune response against viruses relies solely upon sensing of viral genomes and their downstream signaling molecules. Although DNA and RNA viruses are sensed by distinct classes of receptor proteins, there is a possibility of overlap between the viral DNA and viral RNA sensing mechanisms. In this review, we focus on various host sensing molecules and discuss the associated signaling pathways that are activated in response to different viral infections. We further highlight the possibility of crosstalk between the cGAS-STING and the RIG-I-MAVS pathways to limit viral infections. This comprehensive review delineates the mechanisms by which different viruses evade host cellular responses to sustain within the host cells.

DOI: https://doi.org/10.1007/s00705-021-05211-x
Nucleic Acids Res. 2021 Oct 06. pii: gkab901. [Epub ahead of print]

A replication-linked mutational gradient drives somatic mutation accumulation and influences germline polymorphisms and genome composition in mitochondrial DNA.

Monica Sanchez-Contreras, Mariya T Sweetwyne, Brendan F Kohrn, Kristine A Tsantilas, Michael J Hipp, Elizabeth K Schmidt, Jeanne Fredrickson, Jeremy A Whitson, Matthew D Campbell, Peter S Rabinovitch, David J Marcinek, Scott R Kennedy.

Mutations in mitochondrial DNA (mtDNA) cause maternally inherited diseases, while somatic mutations are linked to common diseases of aging. Although mtDNA mutations impact health, the processes that give rise to them are under considerable debate. To investigate the mechanism by which de novo mutations arise, we analyzed the distribution of naturally occurring somatic mutations across the mouse and human mtDNA obtained by Duplex Sequencing. We observe distinct mutational gradients in G→A and T→C transitions delimited by the light-strand origin and the mitochondrial Control Region (mCR). The gradient increases unequally across the mtDNA with age and is lost in the absence of DNA polymerase γ proofreading activity. In addition, high-resolution analysis of the mCR shows that important regulatory elements exhibit considerable variability in mutation frequency, consistent with them being mutational 'hot-spots' or 'cold-spots'. Collectively, these patterns support genome replication via a deamination prone asymmetric strand-displacement mechanism as the fundamental driver of mutagenesis in mammalian DNA. Moreover, the distribution of mtDNA single nucleotide polymorphisms in humans and the distribution of bases in the mtDNA across vertebrate species mirror this gradient, indicating that replication-linked mutations are likely the primary source of inherited polymorphisms that, over evolutionary timescales, influences genome composition during speciation.

DOI: https://doi.org/10.1093/nar/gkab901
J Cell Sci. 2021 Oct 01. pii: jcs240465. [Epub ahead of print]134(19):

Managing risky assets - mitophagy in vivo.

Derek P Narendra.

  Mitochondria, which resemble their α-proteobacteria ancestors, are a major cellular asset, producing energy 'on the cheap' through oxidative phosphorylation. They are also a liability. Increased oxidative phosphorylation means increased oxidative stress, and damaged mitochondria incite inflammation through release of their bacteria-like macromolecules. Mitophagy (the selective macroautophagy of mitochondria) controls mitochondria quality and number to manage these risky assets. Parkin, BNIP3 and NIX were identified as being part of the first mitophagy pathways identified in mammals over a decade ago, with additional pathways, including that mediated by FUNDC1 reported more recently. Loss of Parkin or PINK1 function causes Parkinson's disease, highlighting the importance of mitophagy as a quality control mechanism in the brain. Additionally, mitophagy is induced in idiopathic Parkinson's disease and Alzheimer's disease, protects the heart and other organs against energy stress and lipotoxicity, regulates metabolism by controlling mitochondrial number in brown and beige fat, and clears mitochondria during terminal differentiation of glycolytic cells, such as red blood cells and neurons. Despite its importance in disease, mitophagy is likely dispensable under physiological conditions. This Review explores the in vivo roles of mitophagy in mammalian systems, focusing on the best studied examples - mitophagy in neurodegeneration, cardiomyopathy, metabolism, and red blood cell development - to draw out common themes.

Keywords:  Mitochondria quality control; Neurodegeneration; PRKN; Park2; Park6

DOI:  https://doi.org/10.1242/jcs.240465
Plant Physiol. 2021 Oct 05. 187(2): 769-786

FTSH4 and OMA1 mitochondrial proteases reduce moderate heat stress-induced protein aggregation.

Agata Maziak, Malgorzata Heidorn-Czarna, Aleksandra Weremczuk, Hanna Janska.

The threat of global warming makes uncovering mechanisms of plant tolerance to long-term moderate heat stress particularly important. We previously reported that Arabidopsis (Arabidopsis thaliana) plants lacking mitochondrial proteases FTSH4 or OMA1 suffer phenotypic changes under long-term stress of 30°C, while their growth at 22°C is not affected. Here we found that these morphological and developmental changes are associated with increased accumulation of insoluble mitochondrial protein aggregates that consist mainly of small heat-shock proteins (sHSPs). Greater accumulation of sHSPs in ftsh4 than oma1 corresponds with more severe phenotypic abnormalities. We showed that the proteolytic activity of FTSH4, and to a lesser extent of OMA1, as well as the chaperone function of FTSH4, is crucial for protecting mitochondrial proteins against aggregation. We demonstrated that HSP23.6 and NADH dehydrogenase subunit 9 present in aggregates are proteolytic substrates of FTSH4, and this form of HSP23.6 is also a substrate of OMA1 protease. In addition, we found that the activity of FTSH4 plays an important role during recovery from elevated to optimal temperatures. Isobaric tags for relative and absolute quantification (iTRAQ)-based proteomic analyses, along with identification of aggregation-prone proteins, implicated mitochondrial pathways affected by protein aggregation (e.g. assembly of complex I) and revealed that the mitochondrial proteomes of ftsh4 and oma1 plants are similarly adapted to long-term moderate heat stress. Overall, our data indicate that both FTSH4 and OMA1 increase the tolerance of plants to long-term moderate heat stress by reducing detergent-tolerant mitochondrial protein aggregation.

DOI: https://doi.org/10.1093/plphys/kiab296
Trends Biochem Sci. 2021 Oct 01. pii: S0968-0004(21)00191-2. [Epub ahead of print]

Canary in a coal mine: collided ribosomes as sensors of cellular conditions.

Kyusik Q Kim, Hani S Zaher.

  The recent discovery that collision of ribosomes triggers quality control and stress responses in eukaryotes has shifted the perspective of the field. Collided eukaryotic ribosomes adopt a unique structure, acting as a ubiquitin signaling platform for various response factors. While several of the signals that determine which downstream pathways are activated have been uncovered, we are only beginning to learn how the specificity for the activation of each process is achieved during collisions. This review will summarize those findings and how ribosome-associated factors act as molecular sentinels, linking aberrations in translation to the overall cellular state. Insights into how cells respond to ribosome collision events will provide greater understanding of the role of the ribosome in the maintenance of cellular homeostasis.

Keywords:  collisions; integrated stress response; mRNA surveillance; quality control; ribosome; signaling

DOI:  https://doi.org/10.1016/j.tibs.2021.09.001
Biosci Biotechnol Biochem. 2021 Oct 08. pii: zbab176. [Epub ahead of print]

Natural tetramic acids elicit multiple inhibitory actions against mitochondrial machineries presiding over oxidative phosphorylation.

Yufu Unten, Masatoshi Murai, Katsuyuki Sakai, Yukihiro Asami, Takenori Yamamoto, Takahiro Masuya, Hideto Miyoshi.

  The mitochondrial machineries presiding over ATP synthesis via oxidative phosphorylation are promising druggable targets. Fusaramin, a 3-acyl tetramic acid isolated from Fusarium concentricum FKI-7550, is an inhibitor of oxidative phosphorylation in Saccharomyces cerevisiae mitochondria, although its target has yet to be identified. Fusaramin significantly interfered with [3H]ADP uptake by yeast mitochondria at the concentration range inhibiting oxidative phosphorylation. A photoreactive fusaramin derivative (pFS-5) specifically labeled voltage-dependent anion channel 1 (VDAC1), which facilitates trafficking of ADP/ATP across the outer mitochondrial membrane. These results strongly suggest that the inhibition of oxidative phosphorylation by fusaramin is predominantly attributable to the impairment of VDAC1 functions. Fusaramin also inhibited FoF1-ATP synthase and ubiquinol-cytochrome c oxidoreductase (complex III) at concentrations higher than those required for the VDAC inhibition. Considering that other tetramic acid derivatives are reported to inhibit FoF1-ATP synthase and complex III, natural tetramic acids were found to elicit multiple inhibitory actions against mitochondrial machineries.

Keywords:  VDAC1; fusaramin; mitochondria; oxidative phosphorylation; tetramic acid

DOI:  https://doi.org/10.1093/bbb/zbab176
Redox Biol. 2021 Sep 20. pii: S2213-2317(21)00291-3. [Epub ahead of print]47 102132

Nucleus-mitochondria positive feedback loop formed by ERK5 S496 phosphorylation-mediated poly (ADP-ribose) polymerase activation provokes persistent pro-inflammatory senescent phenotype and accelerates coronary atherosclerosis after chemo-radiation.

Sivareddy Kotla, Aijun Zhang, Masaki Imanishi, Kyung Ae Ko, Steven H Lin, Young Jin Gi, Margie Moczygemba, Sevinj Isgandarova, Keri L Schadler, Caroline Chung, Sarah A Milgrom, Jose Banchs, Syed Wamique Yusuf, Diana N Amaya, Huifang Guo, Tamlyn N Thomas, Ying H Shen, Anita Deswal, Joerg Herrmann, Eugenie S Kleinerman, Mark L Entman, John P Cooke, Giovanni Schifitto, Sanjay B Maggirwar, Elena McBeath, Anisha A Gupte, Sunil Krishnan, Zarana S Patel, Yisang Yoon, Jared K Burks, Keigi Fujiwara, Paul S Brookes, Nhat-Tu Le, Dale J Hamilton, Jun-Ichi Abe.

  The incidence of cardiovascular disease (CVD) is higher in cancer survivors than in the general population. Several cancer treatments are recognized as risk factors for CVD, but specific therapies are unavailable. Many cancer treatments activate shared signaling events, which reprogram myeloid cells (MCs) towards persistent senescence-associated secretory phenotype (SASP) and consequently CVD, but the exact mechanisms remain unclear. This study aimed to provide mechanistic insights and potential treatments by investigating how chemo-radiation can induce persistent SASP. We generated ERK5 S496A knock-in mice and determined SASP in myeloid cells (MCs) by evaluating their efferocytotic ability, antioxidation-related molecule expression, telomere length, and inflammatory gene expression. Candidate SASP inducers were identified by high-throughput screening, using the ERK5 transcriptional activity reporter cell system. Various chemotherapy agents and ionizing radiation (IR) up-regulated p90RSK-mediated ERK5 S496 phosphorylation. Doxorubicin and IR caused metabolic changes with nicotinamide adenine dinucleotide depletion and ensuing mitochondrial stunning (reversible mitochondria dysfunction without showing any cell death under ATP depletion) via p90RSK-ERK5 modulation and poly (ADP-ribose) polymerase (PARP) activation, which formed a nucleus-mitochondria positive feedback loop. This feedback loop reprogramed MCs to induce a sustained SASP state, and ultimately primed MCs to be more sensitive to reactive oxygen species. This priming was also detected in circulating monocytes from cancer patients after IR. When PARP activity was transiently inhibited at the time of IR, mitochondrial stunning, priming, macrophage infiltration, and coronary atherosclerosis were all eradicated. The p90RSK-ERK5 module plays a crucial role in SASP-mediated mitochondrial stunning via regulating PARP activation. Our data show for the first time that the nucleus-mitochondria positive feedback loop formed by p90RSK-ERK5 S496 phosphorylation-mediated PARP activation plays a crucial role of persistent SASP state, and also provide preclinical evidence supporting that transient inhibition of PARP activation only at the time of radiation therapy can prevent future CVD in cancer survivors.

Keywords:  Antioxidants; Atherosclerosis; ERK5; Efferocytosis; Ionizing radiation; Mitochondrial stunning; Poly (ADP-Ribose) polymerase; Senescence-associated secretory phenotype (SASP); Telomere length; p90RSK

DOI:  https://doi.org/10.1016/j.redox.2021.102132
Antioxid Redox Signal. 2021 Oct 04.

The multifaceted ATPase inhibitory factor 1 (IF1) in energy metabolism reprogramming and mitochondrial dysfunction: a new player in age-associated disorders?

Emilia Gore, Thibaut Duparc, Annelise Genoux, Bertrand Perret, Souad Najib, Laurent O Martinez.

Significance The mitochondrial oxidative phosphorylation (OXPHOS) system, comprising the electron transport chain and ATP synthase, generates membrane potential, drives ATP synthesis, governs energy metabolism, and maintains redox balance. OXPHOS dysfunction is associated with a plethora of diseases ranging from rare inherited disorders to common conditions including diabetes, cancer, neurodegenerative diseases, as well as aging. There has been great interest in studying regulators of OXPHOS. Among these, ATPase inhibitory factor 1 (IF1) is an endogenous inhibitor of ATP synthase that has long been thought to avoid the consumption of cellular ATP when ATP synthase acts as an ATP hydrolysis enzyme. Recent Advances Recent data indicates that IF1 inhibits ATP synthesis and is involved in a multitude of mitochondrial-related functions, such as mitochondrial quality control, energy metabolism, redox balance, and cell fate. IF1 also inhibits the ATPase activity of cell-surface ATP synthase, and it is used as a cardiovascular disease biomarker. Critical Issues Although recent data have led to a paradigm shift regarding IF1 functions, these have been poorly studied in entire organisms and in different organs. The understanding of the cellular biology of IF1 is, therefore, still limited. The aim of this review was to provide an overview of the current understanding of the role of IF1 in mitochondrial functions, health, and diseases. Future Directions Further investigations of IF1 functions at the cell, organ, and whole-organism levels and in different pathophysiological conditions will help decipher the controversies surrounding its involvement in mitochondrial function and could unveil therapeutic strategies in human pathology.

DOI: https://doi.org/10.1089/ars.2021.0137
Cell Metab. 2021 Oct 05. pii: S1550-4131(21)00424-1. [Epub ahead of print]33(10): 1903-1905

Targeting senescent immune cells to rejuvenate the aging skeleton.

Ge Zhang, Jin Liu.

Accumulation of senescent cells in the bone marrow leads to age-related bone degeneration. Identifying the key senescent cell types and the factors they release that are responsible for skeletal aging is of keen interest. In a new study by Li et al. (2021), it is shown that immune cells, including neutrophils and macrophages, are critical cell types in this aging process, and that they secrete grancalcin to promote such aging.

DOI: https://doi.org/10.1016/j.cmet.2021.09.005
FEBS J. 2021 Oct 04.

Respiratory Complex I dysfunction in cancer: from a maze of cellular adaptive responses to potential therapeutic strategies.

Manuela Sollazzo, Monica De Luise, Silvia Lemma, Licia Bressi, Maria Iorio, Stefano Miglietta, Sara Milioni, Ivana Kurelac, Luisa Iommarini, Giuseppe Gasparre, Anna Maria Porcelli.

  Mitochondria act as key organelles in cellular bioenergetics and biosynthetic processes producing signals that regulate different molecular networks for proliferation and cell death. This ability is also preserved in pathologic contexts such as tumorigenesis, during which bioenergetic changes and metabolic reprogramming confer flexibility favoring cancer cells survival in a hostile microenvironment. Although different studies epitomize mitochondrial dysfunction as a pro-tumorigenic hit, genetic ablation or pharmacological inhibition of respiratory Complex I causing a severe impairment are associated with a low proliferative phenotype. In this scenario, it must be considered that despite the initial delay in growth, cancer cells may become able to resume proliferation exploiting molecular mechanisms to overcome growth arrest. Here we highlight the current knowledge on molecular responses activated by Complex I-defective cancer cells to bypass physiological control systems and to re-adapt their fitness during microenvironment changes. Such adaptive mechanisms could reveal possible novel molecular players in synthetic lethality with Complex I impairment, thus providing new synergistic strategies for mitochondria-based anti-cancer therapy.

Keywords:  Respiratory complex I; adaptive responses; cancer metabolism; mitochondria; tumor microenvironment

DOI:  https://doi.org/10.1111/febs.16218
Nat Cell Biol. 2021 Oct 06.

Seeking protective mitochondria.

Melina Casadio.

DOI: https://doi.org/10.1038/s41556-021-00771-1
J Cell Biol. 2021 Dec 06. pii: e202006049. [Epub ahead of print]220(12):

PINK1 drives production of mtDNA-containing extracellular vesicles to promote invasiveness.

Nicolas Rabas, Sarah Palmer, Louise Mitchell, Shehab Ismail, Andrea Gohlke, Joel S Riley, Stephen W G Tait, Payam Gammage, Leandro Lemgruber Soares, Iain R Macpherson, Jim C Norman.

The cystine-glutamate antiporter, xCT, supports a glutathione synthesis program enabling cancer cells to cope with metabolically stressful microenvironments. Up-regulated xCT, in combination with glutaminolysis, leads to increased extracellular glutamate, which promotes invasive behavior by activating metabotropic glutamate receptor 3 (mGluR3). Here we show that activation of mGluR3 in breast cancer cells activates Rab27-dependent release of extracellular vesicles (EVs), which can transfer invasive characteristics to "recipient" tumor cells. These EVs contain mitochondrial DNA (mtDNA), which is packaged via a PINK1-dependent mechanism. We highlight mtDNA as a key EV cargo necessary and sufficient for intercellular transfer of invasive behavior by activating Toll-like receptor 9 in recipient cells, and this involves increased endosomal trafficking of pro-invasive receptors. We propose that an EV-mediated mechanism, through which altered cellular metabolism in one cell influences endosomal trafficking in other cells, is key to generation and dissemination of pro-invasive microenvironments during mammary carcinoma progression.

DOI: https://doi.org/10.1083/jcb.202006049
J Biol Chem. 2021 Oct 04. pii: S0021-9258(21)01080-2. [Epub ahead of print] 101277

Modulation of SF3B1 in the pre-mRNA spliceosome induces a RIG-I-dependent type I IFN response.

Aaron Y Chang, Yu Jerry Zhou, Sharanya Iyengar, Piotr W Pobiarzyn, Pavel Tishchenko, Kesha M Shah, Heather Wheeler, Yue-Ming Wang, Paula M Loria, Frank Loganzo, Seng-Ryong Woo.

  Nucleic acid-sensing pathways play critical roles in innate immune activation through the production of type I interferon (IFN-I) and proinflammatory cytokines. These factors are required for effective anti-tumor immune responses. Pharmacological modulators of the pre-mRNA spliceosome splicing factor 3b subunit 1 (SF3B1) are under clinical investigation as cancer cytotoxic agents. However, potential roles of these agents in aberrant RNA generation and subsequent RNA-sensing pathway activation have not been studied. In this study, we observed that SF3B1 pharmacological modulation using pladienolide B (Plad B) induces production of aberrant RNA species and robust IFN-I responses via engagement of the dsRNA sensor retinoic acid-inducible gene I (RIG-I) and downstream interferon regulatory factor 3 (IRF3). We found that Plad B synergized with canonical RIG-I agonism to induce the IFN-I response. In addition, Plad B induced NF-κB responses and secretion of proinflammatory cytokines and chemokines. Finally, we showed that cancer cells bearing the hotspot SF3B1K700E mutation, which leads to global aberrant splicing, had enhanced IFN-I response to canonical RIG-I agonism. Together, these results demonstrate that pharmacological modulation of SF3B1 in cancer cells can induce an enhanced IFN-I response dependent on RIG-I expression. The study suggests that spliceosome modulation may not only induce direct cancer cell cytotoxicity but also initiate an innate immune response via activation of RNA sensing pathways.

Keywords:  Alternative splicing; Anticancer drug; Cytokine; Innate immunity; Interferon; Interferon regulatory factor (IRF); RIG-I-like receptor (RLR); RNA splicing; Spliceosome; mRNA

DOI:  https://doi.org/10.1016/j.jbc.2021.101277
Front Genet. 2021 ;12 734255

Mitonuclear Interactions Produce Diverging Responses to Mild Stress in Drosophila Larvae.

Enrique Rodríguez, Finley Grover Thomas, M Florencia Camus, Nick Lane.

  Mitochondrial function depends on direct interactions between respiratory proteins encoded by genes in two genomes, mitochondrial and nuclear, which evolve in very different ways. Serious incompatibilities between these genomes can have severe effects on development, fitness and viability. The effect of subtle mitonuclear mismatches has received less attention, especially when subject to mild physiological stress. Here, we investigate how two distinct physiological stresses, metabolic stress (high-protein diet) and redox stress [the glutathione precursor N-acetyl cysteine (NAC)], affect development time, egg-to-adult viability, and the mitochondrial physiology of Drosophila larvae with an isogenic nuclear background set against three mitochondrial DNA (mtDNA) haplotypes: one coevolved (WT) and two slightly mismatched (COX and BAR). Larvae fed the high-protein diet developed faster and had greater viability in all haplotypes. The opposite was true of NAC-fed flies, especially those with the COX haplotype. Unexpectedly, the slightly mismatched BAR larvae developed fastest and were the most viable on both treatments, as well as control diets. These changes in larval development were linked to a shift to complex I-driven mitochondrial respiration in all haplotypes on the high-protein diet. In contrast, NAC increased respiration in COX larvae but drove a shift toward oxidation of proline and succinate. The flux of reactive oxygen species was increased in COX larvae treated with NAC and was associated with an increase in mtDNA copy number. Our results support the notion that subtle mitonuclear mismatches can lead to diverging responses to mild physiological stress, undermining fitness in some cases, but surprisingly improving outcomes in other ostensibly mismatched fly lines.

Keywords:  Drosophila melanogaster; N-acetyl cysteine; diet; high-protein; larvae; mitochondria; mitonuclear interactions; oxidative stress

DOI:  https://doi.org/10.3389/fgene.2021.734255
Bioelectrochemistry. 2021 Sep 27. pii: S1567-5394(21)00219-X. [Epub ahead of print]143 107956

Correlated electric field modulation of electron transfer parameters and the access to alternative conformations of multifunctional cytochrome c.

Santiago Oviedo-Rouco, Cecilia Spedalieri, Magalí F Scocozza, Florencia Tomasina, Verónica Tórtora, Rafael Radi, Daniel H Murgida.

  Cytochrome c (Cytc) is a multifunctional protein that, in its native conformation, shuttles electrons in the mitochondrial respiratory chain. Conformational transitions that involve replacement of the heme distal ligand lead to the gain of alternative peroxidase activity, which is crucial for membrane permeabilization during apoptosis. Using a time-resolved SERR spectroelectrochemical approach, we found that the key physicochemical parameters that characterize the electron transfer (ET) canonic function and those that determine the transition to alternative conformations are strongly correlated and are modulated by local electric fields (LEF) of biologically meaningful magnitude. The electron shuttling function is optimized at moderate LEFs of around 1 V nm-1. A decrease of the LEF is detrimental for ET as it rises the reorganization energy. Moreover, LEF values below and above the optimal for ET favor alternative conformations with peroxidase activity and downshifted reduction potentials. The underlying proposed mechanism is the LEF modulation of the flexibility of crucial protein segments, which produces a differential effect on the kinetic ET and conformational parameters of Cytc. These findings might be related to variations in the mitochondrial membrane potential during apoptosis, as the basis for the switch between canonic and alternative functions of Cytc. Moreover, they highlight the possible role of variable LEFs in determining the function of other moonlighting proteins through modulation of the protein dynamics.

Keywords:  Alkaline transition; Cytochrome c; Electric field effects; Protein electron transfer; SERR spectroelectrochemistry

DOI:  https://doi.org/10.1016/j.bioelechem.2021.107956
Plant Physiol. 2021 Oct 05. 187(2): 665-666

If you can't freeze it, chew it: roles of mitochondrial proteases in plant heat stress protection.

Elisa Dell'Aglio.

DOI: https://doi.org/10.1093/plphys/kiab372
Lab Invest. 2021 Oct 04.

ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis.

Kailiang Zhang, Rong Bao, Fengyuan Huang, Kevin Yang, Yishu Ding, Lothar Lauterboeck, Masasuke Yoshida, Qinqiang Long, Qinglin Yang.

Mitochondrial homeostasis is crucial for the function of pancreatic β-cells. ATP synthase inhibitory factor subunit 1 (IF1) is a mitochondrial protein interacting with ATP synthase to inhibit its enzyme activity. IF1 may also play a role in maintaining ATP synthase oligomerization and mitochondrial inner membrane formation. A recent study confirmed IF1 expresses in β-cells. IF1 knockdown in cultured INS-1E β-cells enhances glucose-induced insulin release. However, the role of IF1 in islet β-cells remains little known. The present study investigates islets freshly isolated from mouse lines with global IF1 knockout (IF1-/-) and overexpression (OE). The glucose-stimulated insulin secretion was increased in islets from IF1-/- mice but decreased in islets from IF1 OE mice. Transmitted Electronic Microscopic assessment of isolated islets revealed that the number of matured insulin granules (with dense core) was relatively higher in IF1-/-, but fewer in IF1 OE islets than those of controlled islets. The mitochondrial ultrastructure within β-cells of IF1 overexpressed islets was comparable with those of wild-type mice, whereas those in IF1-/- β-cells showed increased mitochondrial mass. Mitochondrial network analysis in cultured INS-1 β-cells showed a similar pattern with an increased mitochondrial network in IF1 knockdown cells. IF1 overexpressed INS-1 β-cells showed a compromised rate of mitochondrial oxidative phosphorylation with attenuated cellular ATP content. In contrast, INS-1 cells with IF1 knockdown showed markedly increased cellular respiration with improved ATP production. These results support that IF1 is a negative regulator of insulin production and secretion via inhibiting mitochondrial mass and respiration in β-cells. Therefore, inhibiting IF1 to improve β-cell function in patients can be a novel therapeutic strategy to treat diabetes.

DOI: https://doi.org/10.1038/s41374-021-00670-x
Front Oncol. 2021 ;11 747822

The Contribution of Physiological and Accelerated Aging to Cancer Progression Through Senescence-Induced Inflammation.

Jorge Morales-Valencia, Gregory David.

  Senescent cells are found to accumulate in aged individuals, as well as in cancer patients that receive chemotherapeutic treatment. Although originally believed to halt cancer progression due to their characteristic growth arrest, senescent cells remain metabolically active and secrete a combination of inflammatory agents, growth factors and proteases, collectively known as the senescence-associated secretory phenotype (SASP). In this review, we discuss the contribution of senescent cells to cancer progression through their ability to alter cancer cells' properties and to generate a microenvironment that promotes tumor growth. Furthermore, recent evidence suggests that senescent cells are able resume proliferation and drive cancer relapse, pointing to the use of senolytics and SASP modulators as a potential approach to prevent tumor resurgence following treatment cessation. Thus, a better understanding of the hallmarks of senescence and the impact of the SASP will allow the development of improved targeted therapeutic strategies to leverage vulnerabilities associated with this cellular state.

Keywords:  SASP; aging; cancer; inflammation; senescence

DOI:  https://doi.org/10.3389/fonc.2021.747822
Nat Cell Biol. 2021 Oct 06.

Reversible amyloids of pyruvate kinase couple cell metabolism and stress granule disassembly.

Gea Cereghetti, Caroline Wilson-Zbinden, Vera M Kissling, Maren Diether, Alexandra Arm, Haneul Yoo, Ilaria Piazza, Shady Saad, Paola Picotti, D Allan Drummond, Uwe Sauer, Reinhard Dechant, Matthias Peter.

Cells respond to stress by blocking translation, rewiring metabolism and forming transient messenger ribonucleoprotein assemblies called stress granules (SGs). After stress release, re-establishing homeostasis and disassembling SGs requires ATP-consuming processes. However, the molecular mechanisms whereby cells restore ATP production and disassemble SGs after stress remain poorly understood. Here we show that upon stress, the ATP-producing enzyme Cdc19 forms inactive amyloids, and that their rapid re-solubilization is essential to restore ATP production and disassemble SGs in glucose-containing media. Cdc19 re-solubilization is initiated by the glycolytic metabolite fructose-1,6-bisphosphate, which directly binds Cdc19 amyloids, allowing Hsp104 and Ssa2 chaperone recruitment and aggregate re-solubilization. Fructose-1,6-bisphosphate then promotes Cdc19 tetramerization, which boosts its activity to further enhance ATP production and SG disassembly. Together, these results describe a molecular mechanism that is critical for stress recovery and directly couples cellular metabolism with SG dynamics via the regulation of reversible Cdc19 amyloids.

DOI: https://doi.org/10.1038/s41556-021-00760-4
Elife. 2021 Oct 07. pii: e69958. [Epub ahead of print]10

Modulation of fracture healing by the transient accumulation of senescent cells.

Dominik Saul, David G Monroe, Jennifer L Rowsey, Robyn Laura Kosinsky, Stephanie J Vos, Madison L Doolittle, Joshua N Farr, Sundeep Khosla.

  Senescent cells have detrimental effects across tissues with aging but may have beneficial effects on tissue repair, specifically on skin wound healing. However, the potential role of senescent cells in fracture healing has not been defined. Here, we performed an in silico analysis of public mRNAseq data and found that senescence and senescence-associated secretory phenotype (SASP) markers increased during fracture healing. We next directly established that the expression of senescence biomarkers increased markedly during murine fracture healing. We also identified cells in the fracture callus that displayed hallmarks of senescence, including distension of satellite heterochromatin and telomeric DNA damage; the specific identity of these cells, however, requires further characterization. Then, using a genetic mouse model (Cdkn2aLUC) containing a Cdkn2aInk4a-driven luciferase reporter, we demonstrated transient in vivo senescent cell accumulation during callus formation. Finally, we intermittently treated young adult mice following fracture with drugs that selectively eliminate senescent cells ('senolytics', Dasatinib plus Quercetin), and showed that this regimen both decreased senescence and SASP markers in the fracture callus and significantly accelerated the time course of fracture healing. Our findings thus demonstrate that senescent cells accumulate transiently in the murine fracture callus and, in contrast to the skin, their clearance does not impair but rather improves fracture healing.

Keywords:  medicine; mouse

DOI:  https://doi.org/10.7554/eLife.69958