bims-minimp Biomed News
on Mitochondria, innate immunity, proteostasis
Issue of 2022‒05‒01
eleven papers selected by
Hanna Salmonowicz
International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences
  1. Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation.
  2. The role of senescence in cellular plasticity: Lessons from regeneration and development and implications for age-related diseases.
  3. Mitochondrial mutations alter endurance exercise response and determinants in mice.
  4. Atossa: a royal link between OXPHOS metabolism and macrophage migration.
  5. Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel.
  6. Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis.
  7. OXPHOS deficiencies affect peroxisome proliferation by downregulating genes controlled by the SNF1 signaling pathway.
  8. Cotranslational Mechanisms of Protein Biogenesis and Complex Assembly in Eukaryotes.
  9. Mitochondrial hitch-hiking of Pink1 mRNA supports axonal mitophagy.
  10. Mechanisms of ribosome recycling in bacteria and mitochondria: a structural perspective.
  11. Restoring cellular NAD(P)H levels by PPARα and LXRα stimulation to improve mitochondrial complex I deficiency.
  1. Nat Immunol. 2022 Apr 28.
    Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation.
    Leah K Billingham, Joshua S Stoolman, Karthik Vasan, Arianne E Rodriguez, Taylor A Poor, Marten Szibor, Howard T Jacobs, Colleen R Reczek, Aida Rashidi, Peng Zhang, Jason Miska, Navdeep S Chandel.
      The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of the NLRP3 inflammasome through several mechanisms including generation of mitochondrial reactive oxygen species (ROS). Here, we report that mitochondrial electron transport chain (ETC) complex I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase, which can complement the functional loss of mitochondrial complex I or III, respectively, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, the mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP, but via a ROS-independent mechanism.
    DOI:  https://doi.org/10.1038/s41590-022-01185-3
  2. Dev Cell. 2022 Apr 18. pii: S1534-5807(22)00245-3. [Epub ahead of print]
    The role of senescence in cellular plasticity: Lessons from regeneration and development and implications for age-related diseases.
    Nadja Anneliese Ruth Ring, Karla Valdivieso, Johannes Grillari, Heinz Redl, Mikolaj Ogrodnik.
      Senescence is a cellular state which involves cell cycle arrest and a proinflammatory phenotype, and it has traditionally been associated with cellular and organismal aging. However, increasing evidence suggests key roles in tissue growth and regrowth, especially during development and regeneration. Conversely, cellular plasticity-the capacity of cells to undergo identity change, including differentiation and dedifferentiation-is associated with development and regeneration but is now being investigated in the context of age-related diseases such as Alzheimer disease. Here, we discuss the paradox of the role for cellular senescence in cellular plasticity: senescence can act as a cell-autonomous barrier and a paracrine driver of plasticity. We provide a conceptual framework for integrating recent data and use the interplay between cellular senescence and plasticity to provide insight into age-related diseases. Finally, we argue that age-related diseases can be better deciphered when senescence is recognized as a core mechanism of regeneration and development.
    Keywords:  aging; cell plasticity; cellular senescence; differentiation; regeneration; wound healing
    DOI:  https://doi.org/10.1016/j.devcel.2022.04.005
  3. Proc Natl Acad Sci U S A. 2022 May 03. 119(18): e2200549119
    Mitochondrial mutations alter endurance exercise response and determinants in mice.
    Patrick M Schaefer, Komal Rathi, Arrienne Butic, Wendy Tan, Katherine Mitchell, Douglas C Wallace.
      SignificancePrimary mitochondrial diseases (PMDs) are the most prevalent inborn metabolic disorders, affecting an estimated 1 in 4,200 individuals. Endurance exercise is generally known to improve mitochondrial function, but its indication in the heterogeneous group of PMDs is unclear. We determined the relationship between mitochondrial mutations, endurance exercise response, and the underlying molecular pathways in mice with distinct mitochondrial mutations. This revealed that mitochondria are crucial regulators of exercise capacity and exercise response. Endurance exercise proved to be mostly beneficial across the different mitochondrial mutant mice with the exception of a worsened dilated cardiomyopathy in ANT1-deficient mice. Thus, therapeutic exercises, especially in patients with PMDs, should take into account the physical and mitochondrial genetic status of the patient.
    Keywords:  endurance exercise; mitochondrial disease; skeletal muscle adaption
    DOI:  https://doi.org/10.1073/pnas.2200549119
  4. EMBO J. 2022 Apr 25. e111290
    Atossa: a royal link between OXPHOS metabolism and macrophage migration.
    Pedro Latorre-Muro, Pere Puigserver.
      The ability of immune cells to penetrate affected tissues is highly dependent on energy provided by mitochondria, yet their involvement in promoting migration remains unclear. Recent work by Emtenani et al (2022) describes a nuclear Atossa-Porthos axis that adjusts transcription and translation of a small subset of OXPHOS genes to increase mitochondrial bioenergetics and allow macrophage tissue invasion in flies.
    DOI:  https://doi.org/10.15252/embj.2022111290
  5. Nat Chem Biol. 2022 May;18(5): 461-469
    Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel.
    Michael P Murphy, Edward T Chouchani.
      Metabolites once considered solely in catabolism or anabolism turn out to have key regulatory functions. Among these, the citric acid cycle intermediate succinate stands out owing to its multiple roles in disparate pathways, its dramatic concentration changes and its selective cell release. Here we propose that succinate has evolved as a signaling modality because its concentration reflects the coenzyme Q (CoQ) pool redox state, a central redox couple confined to the mitochondrial inner membrane. This connection is of general importance because CoQ redox state integrates three bioenergetic parameters: mitochondrial electron supply, oxygen tension and ATP demand. Succinate, by equilibrating with the CoQ pool, enables the status of this central bioenergetic parameter to be communicated from mitochondria to the rest of the cell, into the circulation and to other cells. The logic of this form of regulation explains many emerging roles of succinate in biology, and suggests future research questions.
    DOI:  https://doi.org/10.1038/s41589-022-01004-8
  6. Nat Commun. 2022 Apr 29. 13(1): 2340
    Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis.
    Vaibhav Sidarala, Jie Zhu, Elena Levi-D'Ancona, Gemma L Pearson, Emma C Reck, Emily M Walker, Brett A Kaufman, Scott A Soleimanpour.
      The dynamin-like GTPases Mitofusin 1 and 2 (Mfn1 and Mfn2) are essential for mitochondrial function, which has been principally attributed to their regulation of fission/fusion dynamics. Here, we report that Mfn1 and 2 are critical for glucose-stimulated insulin secretion (GSIS) primarily through control of mitochondrial DNA (mtDNA) content. Whereas Mfn1 and Mfn2 individually were dispensable for glucose homeostasis, combined Mfn1/2 deletion in β-cells reduced mtDNA content, impaired mitochondrial morphology and networking, and decreased respiratory function, ultimately resulting in severe glucose intolerance. Importantly, gene dosage studies unexpectedly revealed that Mfn1/2 control of glucose homeostasis was dependent on maintenance of mtDNA content, rather than mitochondrial structure. Mfn1/2 maintain mtDNA content by regulating the expression of the crucial mitochondrial transcription factor Tfam, as Tfam overexpression ameliorated the reduction in mtDNA content and GSIS in Mfn1/2-deficient β-cells. Thus, the primary physiologic role of Mfn1 and 2 in β-cells is coupled to the preservation of mtDNA content rather than mitochondrial architecture, and Mfn1 and 2 may be promising targets to overcome mitochondrial dysfunction and restore glucose control in diabetes.
    DOI:  https://doi.org/10.1038/s41467-022-29945-7
  7. Elife. 2022 Apr 25. pii: e75143. [Epub ahead of print]11
    OXPHOS deficiencies affect peroxisome proliferation by downregulating genes controlled by the SNF1 signaling pathway.
    Jean-Claude Farre, Krypton Carolino, Lou Devanneaux, Suresh Subramani.
      How environmental cues influence peroxisome proliferation, particularly through organelles, remains largely unknown. Yeast peroxisomes metabolize fatty acids (FA), and methylotrophic yeasts also metabolize methanol. NADH and acetyl-CoA, produced by these pathways enter mitochondria for ATP production and for anabolic reactions. During the metabolism of FA and/or methanol, the mitochondrial oxidative phosphorylation (OXPHOS) pathway accepts NADH for ATP production and maintains cellular redox balance. Remarkably, peroxisome proliferation in Pichia pastoris was abolished in NADH shuttling- and OXPHOS mutants affecting complex I or III, or by the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), indicating ATP depletion causes the phenotype. We show that mitochondrial OXPHOS deficiency inhibits expression of several peroxisomal proteins implicated in FA and methanol metabolism, as well as in peroxisome division and proliferation. These genes are regulated by the Snf1 complex (SNF1), a pathway generally activated by a high AMP/ATP ratio. In OXPHOS mutants, Snf1 is activated by phosphorylation, but Gal83, its interacting subunit, fails to translocate to the nucleus. Phenotypic defects in peroxisome proliferation observed in the OXPHOS mutants, and phenocopied by the Dgal83 mutant, were rescued by deletion of three transcriptional repressor genes (MIG1, MIG2 and NRG1) controlled by SNF1 signaling. Our results are interpreted in terms of a mechanism by which peroxisomal and mitochondrial proteins and/or metabolites influence redox and energy metabolism, while also influencing peroxisome biogenesis and proliferation, thereby exemplifying interorganellar communication and interplay involving peroxisomes, mitochondria, cytosol and the nucleus. We discuss the physiological relevance of this work in the context of human OXPHOS deficiencies.
    Keywords:  cell biology
    DOI:  https://doi.org/10.7554/eLife.75143
  8. Annu Rev Biomed Data Sci. 2022 Apr 26.
    Cotranslational Mechanisms of Protein Biogenesis and Complex Assembly in Eukaryotes.
    Fabián Morales-Polanco, Jae Ho Lee, Natália M Barbosa, Judith Frydman.
      The formation of protein complexes is crucial to most biological functions. The cellular mechanisms governing protein complex biogenesis are not yet well understood, but some principles of cotranslational and posttranslational assembly are beginning to emerge. In bacteria, this process is favored by operons encoding subunits of protein complexes. Eukaryotic cells do not have polycistronic mRNAs, raising the question of how they orchestrate the encounter of unassembled subunits. Here we review the constraints and mechanisms governing eukaryotic co- and posttranslational protein folding and assembly, including the influence of elongation rate on nascent chain targeting, folding, and chaperone interactions. Recent evidence shows that mRNAs encoding subunits of oligomeric assemblies can undergo localized translation and form cytoplasmic condensates that might facilitate the assembly of protein complexes. Understanding the interplay between localized mRNA translation and cotranslational proteostasis will be critical to defining protein complex assembly in vivo. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 5 is August 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-biodatasci-121721-095858
  9. Autophagy. 2022 Apr 26.
    Mitochondrial hitch-hiking of Pink1 mRNA supports axonal mitophagy.
    Angelika B Harbauer, Thomas L Schwarz.
      Mitostasis, the process of mitochondrial maintenance by biogenesis and degradative mechanisms, is challenged by the extreme length of axons. PINK1 (PTEN induced putative kinase 1) is a mitochondrial protein that targets damaged mitochondria for mitophagy. In reconciling the short half-life of PINK1 with the need for mitophagy of damaged axonal mitochondria, we found that axonal mitophagy depends on local translation of the Pink1 mRNA. Using live-cell imaging, we detected co-transport of the Pink1 mRNA on mitochondria in neurons, which is crucial for mitophagy in distal parts of the cell. Here we discuss how the coupling of the transcript of a short-lived mitochondrial protein to the movement of its target organelles contributes to our understanding of mitostasis in neurons.
    Keywords:  Axonal biology; RNA transport; local translation; mitochondria; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2070332
  10. RNA Biol. 2022 Jan;19(1): 662-677
    Mechanisms of ribosome recycling in bacteria and mitochondria: a structural perspective.
    Savannah M Seely, Matthieu G Gagnon.
      In all living cells, the ribosome translates the genetic information carried by messenger RNAs (mRNAs) into proteins. The process of ribosome recycling, a key step during protein synthesis that ensures ribosomal subunits remain available for new rounds of translation, has been largely overlooked. Despite being essential to the survival of the cell, several mechanistic aspects of ribosome recycling remain unclear. In eubacteria and mitochondria, recycling of the ribosome into subunits requires the concerted action of the ribosome recycling factor (RRF) and elongation factor G (EF-G). Recently, the conserved protein HflX was identified in bacteria as an alternative factor that recycles the ribosome under stress growth conditions. The homologue of HflX, the GTP-binding protein 6 (GTPBP6), has a dual role in mitochondrial translation by facilitating ribosome recycling and biogenesis. In this review, mechanisms of ribosome recycling in eubacteria and mitochondria are described based on structural studies of ribosome complexes.
    Keywords:  GTPBP6; HflX; Ribosome; elongation factor G; protein synthesis; ribosome recycling; ribosome recycling factor; tRNA; translation factors
    DOI:  https://doi.org/10.1080/15476286.2022.2067712
  11. Life Sci. 2022 Apr 22. pii: S0024-3205(22)00271-5. [Epub ahead of print] 120571
    Restoring cellular NAD(P)H levels by PPARα and LXRα stimulation to improve mitochondrial complex I deficiency.
    Sanne J C M Frambach, Ria de Haas, Jan A M Smeitink, Frans G M Russel, Tom J J Schirris.
      Mitochondrial complex I (CI), the first multiprotein enzyme complex of the oxidative phosphorylation system, plays a crucial role in cellular energy production. CI deficiency is associated with a variety of clinical phenotypes, including Leigh syndrome. At the cellular level, an increased NAD(P)H concentration is one of the hallmarks in CI-deficiency.AIMS: Here, we aimed to attenuate increased NAD(P)H levels by stimulation of ATP-dependent cassette (ABC)A1 and ABCG1-mediated cellular cholesterol efflux with various PPARα and LXRα agonists.
    MAIN METHODS: Mitochondrial CI-deficient fibroblasts and chemically-induced CI-deficient HeLa cells were used to study the dose-dependent effects of various PPARα and LXRα on cellular NAD(P)H levels and cholesterol efflux.
    KEY FINDINGS: In patient-derived mitochondrial CI-deficient fibroblasts, GW590735, astaxanthin, oleoylethanolamide, and GW3965 significantly reduced the enhanced NAD(P)H levels in CI-deficient fibroblasts. Similar effects were observed in chemically-induced CI-impaired HeLa cells, in which BMS-687453, Wy14643, GW7647, T0901317, DMHCA also demonstrated a beneficial effect. Surprisingly, no effect on ABCA1- and ABCG1-mediated cholesterol efflux in HeLa cells and fibroblasts was found after treatment with these compounds. The reduction in NAD(P)H levels by GW590735 could be partially reversed by inhibition of fatty acid synthase and β-oxidation, which suggests that its beneficial effects are possibly mediated via stimulation of fatty acid metabolism rather than cholesterol efflux.
    SIGNIFICANCE: Collectively, PPARα and LXRα stimulation resulted in attenuated cellular NAD(P)H levels in CI-impaired HeLa cells and patient-derived fibroblasts and could eventually have a therapeutic potential in CI deficiency.
    Keywords:  Liver X receptor α; Mitochondrial complex I deficiency; Nicotinamide adenine dinucleotide (phosphate); Peroxisome proliferator activated receptor α; Redox state
    DOI:  https://doi.org/10.1016/j.lfs.2022.120571
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