bims-minimp Biomed News
on Mitochondria, innate immunity, proteostasis
Issue of 2021‒11‒28
forty-three papers selected by
Hanna Salmonowicz
International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences
  1. Molecular Mechanisms of mtDNA-Mediated Inflammation.
  2. ER-associated CTRP1 regulates mitochondrial fission via interaction with DRP1.
  3. The Role of Immune Cells in Oxi-Inflamm-Aging.
  4. Targeting Mitochondrial Metabolism as a Strategy to Treat Senescence.
  5. A new automated tool to quantify nucleoid distribution within mitochondrial networks.
  6. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
  7. The role of protein acetylation in regulating mitochondrial fusion and fission.
  8. Cellular senescence links mitochondria-ER contacts and aging.
  9. The Molecular Assembly State of Drp1 Controls its Association With the Mitochondrial Recruitment Receptors Mff and MIEF1/2.
  10. A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy.
  11. The TFAM-to-mtDNA ratio defines inner-cellular nucleoid populations with distinct activity levels.
  12. GRP75 Regulates Mitochondrial-Supercomplex Turnover to Modulate Insulin Sensitivity.
  13. TRAP1 in Oxidative Stress and Neurodegeneration.
  14. Monitoring checkpoints of metabolism and protein biogenesis in mitochondria by Phos-tag technology.
  15. The Multifaceted Regulation of Mitochondrial Dynamics During Mitosis.
  16. Adipocyte extracellular vesicles: rescuers of cardiac mitochondrial stress.
  17. Coenzyme Q at the Hinge of Health and Metabolic Diseases.
  18. Herpes Simplex Virus Type 1 Infection Disturbs the Mitochondrial Network, Leading to Type I Interferon Production through the RNA Polymerase III/RIG-I Pathway.
  19. LARP7 ameliorates cellular senescence and aging by allosterically enhancing SIRT1 deacetylase activity.
  20. Mitochondrial regulation and white adipose tissue homeostasis.
  21. Mitochondrial Quality Control in the Maintenance of Cardiovascular Homeostasis: The Roles and Interregulation of UPS, Mitochondrial Dynamics and Mitophagy.
  22. RIG-I Deficiency Promotes Obesity-Induced Insulin Resistance.
  23. Gaining Insight into Mitochondrial Genetic Variation and Downstream Pathophysiology: What Can i(PSCs) Do?
  24. Immune system cells from COVID-19 patients display compromised mitochondrial-nuclear expression co-regulation and rewiring towards glycolysis.
  25. On the Role of the Immunoproteasome in Protein Homeostasis.
  26. MicroRNA-101-3p Modulates Mitochondrial Metabolism via the Regulation of Complex II Assembly.
  27. Impaired TFAM expression promotes mitochondrial damage to drive fibroblast activation and fibrosis in systemic sclerosis.
  28. Hormonal Regulation of Oxidative Phosphorylation in the Brain in Health and Disease.
  29. Footprints of a microbial toxin from the gut microbiome to mesencephalic mitochondria.
  30. MiR 208a Regulates Mitochondrial Biogenesis in Metabolically Challenged Cardiomyocytes.
  31. Role of haematopoietic cell-specific protein 1-associated protein X-1 gene in lipopolysaccharide-induced apoptosis of human dermal fibroblasts.
  32. Molecular characteristics of proteins within the mitochondrial Fe-S cluster assembly complex.
  33. Rewiring cell signalling pathways in pathogenic mtDNA mutations.
  34. Let's talk about healthy aging (but where to begin?).
  35. Hematopoiesis under telomere attrition at the single-cell resolution.
  36. How Immunosenescence and Inflammaging May Contribute to Hyperinflammatory Syndrome in COVID-19.
  37. Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation.
  38. The Interactions between Nanoparticles and the Innate Immune System from a Nanotechnologist Perspective.
  39. Metabolism of cancer cells commonly responds to irradiation by a transient early mitochondrial shutdown.
  40. SUMO orchestrates multiple alternative DNA-protein crosslink repair pathways.
  41. TWIST1 controls cellular senescence and energy metabolism in mesenchymal stem cells.
  42. Abnormal mitochondrial structure and function are retained in gingival tissues and human gingival fibroblasts from patients with chronic periodontitis.
  43. A redox cycle with complex II prioritizes sulfide quinone oxidoreductase dependent H2S oxidation.
  1. Cells. 2021 Oct 26. pii: 2898. [Epub ahead of print]10(11):
    Molecular Mechanisms of mtDNA-Mediated Inflammation.
    Anna De Gaetano, Kateryna Solodka, Giada Zanini, Valentina Selleri, Anna Vittoria Mattioli, Milena Nasi, Marcello Pinti.
      Besides their role in cell metabolism, mitochondria display many other functions. Mitochondrial DNA (mtDNA), the own genome of the organelle, plays an important role in modulating the inflammatory immune response. When released from the mitochondrion to the cytosol, mtDNA is recognized by cGAS, a cGAMP which activates a pathway leading to enhanced expression of type I interferons, and by NLRP3 inflammasome, which promotes the activation of pro-inflammatory cytokines Interleukin-1beta and Interleukin-18. Furthermore, mtDNA can be bound by Toll-like receptor 9 in the endosome and activate a pathway that ultimately leads to the expression of pro-inflammatory cytokines. mtDNA is released in the extracellular space in different forms (free DNA, protein-bound DNA fragments) either as free circulating molecules or encapsulated in extracellular vesicles. In this review, we discussed the latest findings concerning the molecular mechanisms that regulate the release of mtDNA from mitochondria, and the mechanisms that connect mtDNA misplacement to the activation of inflammation in different pathophysiological conditions.
    Keywords:  STING; TLR9; extracellular cf-mtDNA; inflammasome; mitochondria; mtDNA
    DOI:  https://doi.org/10.3390/cells10112898
  2. Exp Mol Med. 2021 Nov 26.
    ER-associated CTRP1 regulates mitochondrial fission via interaction with DRP1.
    Seong Keun Sonn, Seungwoon Seo, Jaemoon Yang, Ki Sook Oh, Hsiuchen Chen, David C Chan, Kunsoo Rhee, Kyung S Lee, Young Yang, Goo Taeg Oh.
      C1q/TNF-related protein 1 (CTRP1) is a CTRP family member that has collagenous and globular C1q-like domains. The secreted form of CTRP1 is known to be associated with cardiovascular and metabolic diseases, but its cellular roles have not yet been elucidated. Here, we showed that cytosolic CTRP1 localizes to the endoplasmic reticulum (ER) membrane and that knockout or depletion of CTRP1 leads to mitochondrial fission defects, as demonstrated by mitochondrial elongation. Mitochondrial fission events are known to occur through an interaction between mitochondria and the ER, but we do not know whether the ER and/or its associated proteins participate directly in the entire mitochondrial fission event. Interestingly, we herein showed that ablation of CTRP1 suppresses the recruitment of DRP1 to mitochondria and provided evidence suggesting that the ER-mitochondrion interaction is required for the proper regulation of mitochondrial morphology. We further report that CTRP1 inactivation-induced mitochondrial fission defects induce apoptotic resistance and neuronal degeneration, which are also associated with ablation of DRP1. These results demonstrate for the first time that cytosolic CTRP1 is an ER transmembrane protein that acts as a key regulator of mitochondrial fission, providing new insight into the etiology of metabolic and neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s12276-021-00701-z
  3. Cells. 2021 Nov 01. pii: 2974. [Epub ahead of print]10(11):
    The Role of Immune Cells in Oxi-Inflamm-Aging.
    Irene Martínez de Toda, Noemi Ceprián, Estefanía Díaz-Del Cerro, Mónica De la Fuente.
      Aging is the result of the deterioration of the homeostatic systems (nervous, endocrine, and immune systems), which preserve the organism's health. We propose that the age-related impairment of these systems is due to the establishment of a chronic oxidative stress situation that leads to low-grade chronic inflammation throughout the immune system's activity. It is known that the immune system weakens with age, which increases morbidity and mortality. In this context, we describe how the function of immune cells can be used as an indicator of the rate of aging of an individual. In addition to this passive role as a marker, we describe how the immune system can work as a driver of aging by amplifying the oxidative-inflammatory stress associated with aging (oxi-inflamm-aging) and inducing senescence in far tissue cells. Further supporting our theory, we discuss how certain lifestyle conditions (such as social environment, nutrition, or exercise) can have an impact on longevity by affecting the oxidative and inflammatory state of immune cells, regulating immunosenescence and its contribution to oxi-inflamm-aging.
    Keywords:  aging; biological age; immune cells; inflammatory stress; oxidative stress
    DOI:  https://doi.org/10.3390/cells10112974
  4. Cells. 2021 Nov 03. pii: 3003. [Epub ahead of print]10(11):
    Targeting Mitochondrial Metabolism as a Strategy to Treat Senescence.
    Yun Haeng Lee, Ji Yun Park, Haneur Lee, Eun Seon Song, Myeong Uk Kuk, Junghyun Joo, Sekyung Oh, Hyung Wook Kwon, Joon Tae Park, Sang Chul Park.
      Mitochondria are one of organelles that undergo significant changes associated with senescence. An increase in mitochondrial size is observed in senescent cells, and this increase is ascribed to the accumulation of dysfunctional mitochondria that generate excessive reactive oxygen species (ROS). Such dysfunctional mitochondria are prime targets for ROS-induced damage, which leads to the deterioration of oxidative phosphorylation and increased dependence on glycolysis as an energy source. Based on findings indicating that senescent cells exhibit mitochondrial metabolic alterations, a strategy to induce mitochondrial metabolic reprogramming has been proposed to treat aging and age-related diseases. In this review, we discuss senescence-related mitochondrial changes and consequent mitochondrial metabolic alterations. We assess the significance of mitochondrial metabolic reprogramming for senescence regulation and propose the appropriate control of mitochondrial metabolism to ameliorate senescence. Learning how to regulate mitochondrial metabolism will provide knowledge for the control of aging and age-related pathologies. Further research focusing on mitochondrial metabolic reprogramming will be an important guide for the development of anti-aging therapies, and will provide novel strategies for anti-aging interventions.
    Keywords:  ROS; mitochondria; mitochondrial metabolic reprogramming; senescence amelioration
    DOI:  https://doi.org/10.3390/cells10113003
  5. Sci Rep. 2021 Nov 23. 11(1): 22755
    A new automated tool to quantify nucleoid distribution within mitochondrial networks.
    Hema Saranya Ilamathi, Mathieu Ouellet, Rasha Sabouny, Justine Desrochers-Goyette, Matthew A Lines, Gerald Pfeffer, Timothy E Shutt, Marc Germain.
      Mitochondrial DNA (mtDNA) maintenance is essential to sustain a functionally healthy population of mitochondria within cells. Proper mtDNA replication and distribution within mitochondrial networks are essential to maintain mitochondrial homeostasis. However, the fundamental basis of mtDNA segregation and distribution within mitochondrial networks is still unclear. To address these questions, we developed an algorithm, Mitomate tracker to unravel the global distribution of nucleoids within mitochondria. Using this tool, we decipher the semi-regular spacing of nucleoids across mitochondrial networks. Furthermore, we show that mitochondrial fission actively regulates mtDNA distribution by controlling the distribution of nucleoids within mitochondrial networks. Specifically, we found that primary cells bearing disease-associated mutations in the fission proteins DRP1 and MYH14 show altered nucleoid distribution, and acute enrichment of enlarged nucleoids near the nucleus. Further analysis suggests that the altered nucleoid distribution observed in the fission mutants is the result of both changes in network structure and nucleoid density. Thus, our study provides novel insights into the role of mitochondria fission in nucleoid distribution and the understanding of diseases caused by fission defects.
    DOI:  https://doi.org/10.1038/s41598-021-01987-9
  6. Cell Metab. 2021 Nov 12. pii: S1550-4131(21)00529-5. [Epub ahead of print]
    Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
    Marcel Morgenstern, Christian D Peikert, Philipp Lübbert, Ida Suppanz, Cinzia Klemm, Oliver Alka, Conny Steiert, Nataliia Naumenko, Alexander Schendzielorz, Laura Melchionda, Wignand W D Mühlhäuser, Bettina Knapp, Jakob D Busch, Sebastian B Stiller, Stefan Dannenmaier, Caroline Lindau, Mariya Licheva, Christopher Eickhorst, Riccardo Galbusera, Ralf M Zerbes, Michael T Ryan, Claudine Kraft, Vera Kozjak-Pavlovic, Friedel Drepper, Sven Dennerlein, Silke Oeljeklaus, Nikolaus Pfanner, Nils Wiedemann, Bettina Warscheid.
      Mitochondria are key organelles for cellular energetics, metabolism, signaling, and quality control and have been linked to various diseases. Different views exist on the composition of the human mitochondrial proteome. We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). We identified interactors of translocases, respiratory chain, and ATP synthase assembly factors. The abundance of MitoCoP proteins covers six orders of magnitude and amounts to 7% of the cellular proteome with the chaperones HSP60-HSP10 being the most abundant mitochondrial proteins. MitoCoP dynamics spans three orders of magnitudes, with half-lives from hours to months, and suggests a rapid regulation of biosynthesis and assembly processes. 460 MitoCoP genes are linked to human diseases with a strong prevalence for the central nervous system and metabolism. MitoCoP will provide a high-confidence resource for placing dynamics, functions, and dysfunctions of mitochondria into the cellular context.
    Keywords:  Mitochondria; complexome; copy numbers; disease; half-lives; high-confidence proteome; human cells; protein translocation; respiratory chain; smORFs
    DOI:  https://doi.org/10.1016/j.cmet.2021.11.001
  7. Biochem Soc Trans. 2021 Nov 23. pii: BST20210798. [Epub ahead of print]
    The role of protein acetylation in regulating mitochondrial fusion and fission.
    Golam M Uddin, Rafa Abbas, Timothy E Shutt.
      The dynamic processes of mitochondrial fusion and fission determine the shape of mitochondria, which can range from individual fragments to a hyperfused network, and influence mitochondrial function. Changes in mitochondrial shape can occur rapidly, allowing mitochondria to adapt to specific cues and changing cellular demands. Here, we will review what is known about how key proteins required for mitochondrial fusion and fission are regulated by their acetylation status, with acetylation promoting fission and deacetylation enhancing fusion. In particular, we will examine the roles of NAD+ dependant sirtuin deacetylases, which mediate mitochondrial acetylation, and how this post-translational modification provides an exquisite regulatory mechanism to co-ordinate mitochondrial function with metabolic demands of the cell.
    Keywords:  acetylation/deacetylation; fission; fusion; mitochondria; sirtuins
    DOI:  https://doi.org/10.1042/BST20210798
  8. Commun Biol. 2021 Nov 24. 4(1): 1323
    Cellular senescence links mitochondria-ER contacts and aging.
    Dorian V Ziegler, Nadine Martin, David Bernard.
      Membrane contact sites emerged in the last decade as key players in the integration, regulation and transmission of many signals within cells, with critical impact in multiple pathophysiological contexts. Numerous studies accordingly point to a role for mitochondria-endoplasmic reticulum contacts (MERCs) in modulating aging. Nonetheless, the driving cellular mechanisms behind this role remain unclear. Recent evidence unravelled that MERCs regulate cellular senescence, a state of permanent proliferation arrest associated with a pro-inflammatory secretome, which could mediate MERC impact on aging. Here we discuss this idea in light of recent advances supporting an interplay between MERCs, cellular senescence and aging.
    DOI:  https://doi.org/10.1038/s42003-021-02840-5
  9. Front Cell Dev Biol. 2021 ;9 706687
    The Molecular Assembly State of Drp1 Controls its Association With the Mitochondrial Recruitment Receptors Mff and MIEF1/2.
    Rong Yu, Shao-Bo Jin, Maria Ankarcrona, Urban Lendahl, Monica Nistér, Jian Zhao.
      Drp1 is a central player in mitochondrial fission and is recruited to mitochondria by Mff and MIEFs (MIEF1 and MIEF2), but little is known about how its assembly state affects Drp1 mitochondrial recruitment and fission. Here, we used in vivo chemical crosslinking to explore the self-assembly state of Drp1 and how it regulates the association of Drp1 with MIEFs and Mff. We show that in intact mammalian cells Drp1 exists as a mixture of multiple self-assembly forms ranging from the minimal, probably tetrameric, self-assembly subunit to several higher order oligomers. Precluding mitochondria-bound Drp1 in Mff/MIEF1/2-deficient cells does not affect the oligomerization state of Drp1, while conversely forced recruitment of Drp1 to mitochondria by MIEFs or Mff facilitates Drp1 oligomerization. Mff preferentially binds to higher order oligomers of Drp1, whereas MIEFs bind to a wider-range of Drp1 assembly subunits, including both lower and higher oligomeric states. Mff only recruits active forms of Drp1, while MIEFs are less selective and recruit both active and inactive Drp1 as well as oligomerization- or GTPase-deficient Drp1 mutants to mitochondria. Moreover, all the fission-incompetent Drp1 mutants tested (except the monomeric mutant K668E) affect Drp1-driven mitochondrial dynamics via incorporation of the mutants into the native oligomers to form function-deficient Drp1 assemblies. We here confirm that MIEFs also serve as a platform facilitating the binding of Drp1 to Mff and loss of MIEFs severely impairs the interaction between Drp1 and Mff. Collectively, our findings suggest that Mff and MIEFs respond differently to the molecular assembly state of Drp1 and that the extent of Drp1 oligomerization regulates mitochondrial dynamics.
    Keywords:  Drp1; Drp1 mutation; MIEF1; MIEF2; Mff; mitochondria; mitochondrial dynamics; oligomerization
    DOI:  https://doi.org/10.3389/fcell.2021.706687
  10. Redox Biol. 2021 Nov 11. pii: S2213-2317(21)00346-3. [Epub ahead of print]48 102186
    A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy.
    Akbar Zeb, Vinay Choubey, Ruby Gupta, Malle Kuum, Dzhamilja Safiulina, Annika Vaarmann, Nana Gogichaishvili, Mailis Liiv, Ivar Ilves, Kaido Tämm, Vladimir Veksler, Allen Kaasik.
      When ROS production exceeds the cellular antioxidant capacity, the cell needs to eliminate the defective mitochondria responsible for excessive ROS production. It has been proposed that the removal of these defective mitochondria involves mitophagy, but the mechanism of this regulation remains unclear. Here, we demonstrate that moderate mitochondrial superoxide and hydrogen peroxide production oxidates KEAP1, thus breaking the interaction between this protein and PGAM5, leading to the inhibition of its proteasomal degradation. Accumulated PGAM5 interferes with the processing of the PINK1 in the mitochondria leading to the accumulation of PINK1 on the outer mitochondrial membrane. In turn, PINK1 promotes Parkin recruitment to mitochondria and sensitizes mitochondria for autophagic removal. We also demonstrate that inhibitors of the KEAP1-PGAM5 protein-protein interaction (including CPUY192018) mimic the effect of mitochondrial ROS and sensitize mitophagy machinery, suggesting that these inhibitors could be used as pharmacological regulators of mitophagy. Together, our results show that KEAP1/PGAM5 complex senses mitochondrially generated superoxide/hydrogen peroxide to induce mitophagy.
    Keywords:  Mitophagy; NRF2/KEAP1 pathway; Neurodegenerative diseases; Oxidative stress; PINK1/Parkin pathway
    DOI:  https://doi.org/10.1016/j.redox.2021.102186
  11. Cell Rep. 2021 Nov 23. pii: S2211-1247(21)01479-0. [Epub ahead of print]37(8): 110000
    The TFAM-to-mtDNA ratio defines inner-cellular nucleoid populations with distinct activity levels.
    Christian Brüser, Jan Keller-Findeisen, Stefan Jakobs.
      In human cells, generally a single mitochondrial DNA (mtDNA) is compacted into a nucleoprotein complex denoted the nucleoid. Each cell contains hundreds of nucleoids, which tend to cluster into small groups. It is unknown whether all nucleoids are equally involved in mtDNA replication and transcription or whether distinct nucleoid subpopulations exist. Here, we use multi-color STED super-resolution microscopy to determine the activity of individual nucleoids in primary human cells. We demonstrate that only a minority of all nucleoids are active. Active nucleoids are physically larger and tend to be involved in both replication and transcription. Inactivity correlates with a high ratio of the mitochondrial transcription factor A (TFAM) to the mtDNA of the individual nucleoid, suggesting that TFAM-induced nucleoid compaction regulates nucleoid replication and transcription activity in vivo. We propose that the stable population of highly compacted inactive nucleoids represents a storage pool of mtDNAs with a lower mutational load.
    Keywords:  DNA packaging; STED nanoscopy; mitochondrial gene expression; mtDNA mutations; mtDNA replication
    DOI:  https://doi.org/10.1016/j.celrep.2021.110000
  12. Diabetes. 2021 Nov 22. pii: db210173. [Epub ahead of print]
    GRP75 Regulates Mitochondrial-Supercomplex Turnover to Modulate Insulin Sensitivity.
    Qiongya Zhao, Ting Luo, Feng Gao, Yinxu Fu, Bin Li, Xiaoli Shao, Haifeng Chen, Zhuohua Zhou, Sihan Guo, Lijun Shen, Liqin Jin, Dong Cen, Huaibin Zhou, Jianxin Lyu, Hezhi Fang.
      GRP75, defined as a major component of both mitochondrial quality control system and mitochondria-associated membrane, plays a key role in mitochondrial homeostasis. In this study, we assessed the roles of GRP75, other than as a component, in insulin action in both in vitro and in vivo models with insulin resistance. We found that GRP75 was downregulated in HFD-fed mice, and induction of Grp75 in mice could prevent HFD induced obesity and insulin resistance. Mechanistically, GRP75 influenced insulin sensitivity by regulating mitochondrial function through its modulation of mitochondrial-supercomplex turnover rather than MAM communication: GRP75 was negatively associated with respiratory-chain complex activity and was essential for mitochondrial-supercomplex assembly and stabilization. Moreover, mitochondrial dysfunction in Grp75-knockdown cells might further increase mitochondrial fragmentation, thus trigger cytosolic mitochondrial DNA release and activate the cGAS/STING-dependent pro-inflammatory response. Therefore, GRP75 can serve as a potential therapeutic target of insulin resistant-related diabetes or other metabolic diseases.
    DOI:  https://doi.org/10.2337/db21-0173
  13. Antioxidants (Basel). 2021 Nov 19. pii: 1829. [Epub ahead of print]10(11):
    TRAP1 in Oxidative Stress and Neurodegeneration.
    Inês Ramos Rego, Beatriz Santos Cruz, António Francisco Ambrósio, Celso Henrique Alves.
      Tumor necrosis factor receptor-associated protein 1 (TRAP1), also known as heat shock protein 75 (HSP75), is a member of the heat shock protein 90 (HSP90) chaperone family that resides mainly in the mitochondria. As a mitochondrial molecular chaperone, TRAP1 supports protein folding and contributes to the maintenance of mitochondrial integrity even under cellular stress. TRAP1 is a cellular regulator of mitochondrial bioenergetics, redox homeostasis, oxidative stress-induced cell death, apoptosis, and unfolded protein response (UPR) in the endoplasmic reticulum (ER). TRAP1 has attracted increasing interest as a therapeutical target, with a special focus on the design of TRAP1 specific inhibitors. Although TRAP1 was extensively studied in the oncology field, its role in central nervous system cells, under physiological and pathological conditions, remains largely unknown. In this review, we will start by summarizing the biology of TRAP1, including its structure and related pathways. Thereafter, we will continue by debating the role of TRAP1 in the maintenance of redox homeostasis and protection against oxidative stress and apoptosis. The role of TRAP1 in neurodegenerative disorders will also be discussed. Finally, we will review the potential of TRAP1 inhibitors as neuroprotective drugs.
    Keywords:  HSP75; HSP90; TRAP1; mitochondria; neurodegeneration; oxidative stress
    DOI:  https://doi.org/10.3390/antiox10111829
  14. J Proteomics. 2021 Nov 20. pii: S1874-3919(21)00329-8. [Epub ahead of print] 104430
    Monitoring checkpoints of metabolism and protein biogenesis in mitochondria by Phos-tag technology.
    Corvin Walter, Adinarayana Marada, Chris Meisinger.
      A role for reversible phosphorylation in regulation of mitochondrial proteins has been neglected for a long time. Particularly, the import machineries that mediate influx of more than 1000 different precursor proteins into the organelle were considered as predominantly constitutively active entities. Only recently, a combination of advanced phosphoproteomic approaches and Phos-tag technology enabled the discovery of several phosphorylation sites at the translocase of the outer membrane TOM and the identification of cellular signalling cascades that allow dynamic adaptation of the protein influx into mitochondria upon changing cellular demands. Here, we present a protocol that allows biochemical and semi-quantitative profiling of intra-mitochondrial protein phosphorylation. We exemplify this with the pyruvate dehydrogenase complex (PDH), which serves as a central metabolic switch in energy metabolism that is based on reversible phosphorylation. Phos-tag technology allows rapid monitoring of the metabolic state via simultaneous detection of phosphorylated and non-phosphorylated species of the PDH core component Pda1. Our protocol can be applied for several further intra-organellar proteins like respiratory chain complexes or protein translocases of the inner membrane. SIGNIFICANCE: Our manuscript describes for the first time how Phos-tag technology can be applied to monitor phosphorylation of intramitochondrial proteins. We exemplify this with the regulation of the pyruvate dehydrogenase complex as central regulatory switch in energy metabolism. We show that our protocol allows a rapid monitoring of the metabolic state of the cell (phosphorylated PDH is inactive while non-phosphorylated PDH is active) and can be applied for rapid profiling of different metabolic conditions as well as for profiling phosphorylation of further intramitochondrial protein (complexes).
    Keywords:  Mitochondria; Protein import; Protein translocation; Signalling; TOM complex
    DOI:  https://doi.org/10.1016/j.jprot.2021.104430
  15. Front Cell Dev Biol. 2021 ;9 767221
    The Multifaceted Regulation of Mitochondrial Dynamics During Mitosis.
    Evanthia Pangou, Izabela Sumara.
      Mitosis ensures genome integrity by mediating precise segregation of the duplicated genetic material. Segregation of subcellular organelles during mitosis also needs to be tightly coordinated in order to warrant their proper inheritance and cellular homeostasis. The inheritance of mitochondria, a powerhouse of the cell, is tightly regulated in order to meet the high energy demand to fuel the mitotic machinery. Mitochondria are highly dynamic organelles, which undergo events of fission, fusion and transport during different cell cycle stages. Importantly, during mitosis several kinases phosphorylate the key mitochondrial factors and drive fragmentation of mitochondria to allow for their efficient distribution and inheritance to two daughter cells. Recent evidence suggests that mitochondrial fission can also actively contribute to the regulation of mitotic progression. This review aims at summarizing established and emerging concepts about the complex regulatory networks which couple crucial mitotic factors and events to mitochondrial dynamics and which could be implicated in human disease.
    Keywords:  disease; fission; fusion; mitochondria; mitosis; transport
    DOI:  https://doi.org/10.3389/fcell.2021.767221
  16. Trends Endocrinol Metab. 2021 Nov 18. pii: S1043-2760(21)00258-7. [Epub ahead of print]
    Adipocyte extracellular vesicles: rescuers of cardiac mitochondrial stress.
    Xavier Loyer, Chantal M Boulanger, Soazig Le Lay.
      Nutrient excess induces mitochondrial dysfunction, which participates in obesity-related complications. Obesity also associates with high cardiac oxidative stress, which contributes to myocardial dysfunction. Crewe et al. recently evidenced the pivotal role of adipocyte-derived extracellular vesicles (EVs) in cardiac oxidative stress responses and revealed their unexpected protective effect against ischemia/reperfusion injury.
    Keywords:  adipocyte; cardiomyocyte; extracellular vesicle; heart; mitochondria
    DOI:  https://doi.org/10.1016/j.tem.2021.11.001
  17. Antioxidants (Basel). 2021 Nov 08. pii: 1785. [Epub ahead of print]10(11):
    Coenzyme Q at the Hinge of Health and Metabolic Diseases.
    Juan Diego Hernández-Camacho, Laura García-Corzo, Daniel José Moreno Fernández-Ayala, Plácido Navas, Guillermo López-Lluch.
      Coenzyme Q is a unique lipidic molecule highly conserved in evolution and essential to maintaining aerobic metabolism. It is endogenously synthesized in all cells by a very complex pathway involving a group of nuclear genes that share high homology among species. This pathway is tightly regulated at transcription and translation, but also by environment and energy requirements. Here, we review how coenzyme Q reacts within mitochondria to promote ATP synthesis and also integrates a plethora of metabolic pathways and regulates mitochondrial oxidative stress. Coenzyme Q is also located in all cellular membranes and plasma lipoproteins in which it exerts antioxidant function, and its reaction with different extramitochondrial oxidoreductases contributes to regulate the cellular redox homeostasis and cytosolic oxidative stress, providing a key factor in controlling various apoptosis mechanisms. Coenzyme Q levels can be decreased in humans by defects in the biosynthesis pathway or by mitochondrial or cytosolic dysfunctions, leading to a highly heterogeneous group of mitochondrial diseases included in the coenzyme Q deficiency syndrome. We also review the importance of coenzyme Q levels and its reactions involved in aging and age-associated metabolic disorders, and how the strategy of its supplementation has had benefits for combating these diseases and for physical performance in aging.
    Keywords:  coenzyme Q; metabolic disease; mitochondria; rare disease; ubiquinone
    DOI:  https://doi.org/10.3390/antiox10111785
  18. mBio. 2021 Nov 23. e0255721
    Herpes Simplex Virus Type 1 Infection Disturbs the Mitochondrial Network, Leading to Type I Interferon Production through the RNA Polymerase III/RIG-I Pathway.
    Noémie Berry, Rodolphe Suspène, Vincent Caval, Pierre Khalfi, Guillaume Beauclair, Stéphane Rigaud, Hervé Blanc, Marco Vignuzzi, Simon Wain-Hobson, Jean-Pierre Vartanian.
      Viruses have evolved a plethora of mechanisms to impair host innate immune responses. Herpes simplex virus type 1 (HSV-1), a double-stranded linear DNA virus, impairs the mitochondrial network and dynamics predominantly through the UL12.5 gene. We demonstrated that HSV-1 infection induced a remodeling of mitochondrial shape, resulting in a fragmentation of the mitochondria associated with a decrease in their volume and an increase in their sphericity. This damage leads to the release of mitochondrial DNA (mtDNA) to the cytosol. By generating a stable THP-1 cell line expressing the DNase I-mCherry fusion protein and a THP-1 cell line specifically depleted of mtDNA upon ethidium bromide treatment, we showed that cytosolic mtDNA contributes to type I interferon and APOBEC3A upregulation. This was confirmed by using an HSV-1 strain (KOS37 UL98-SPA) with a deletion of the UL12.5 gene that impaired its ability to induce mtDNA stress. Furthermore, by using an inhibitor of RNA polymerase III, we demonstrated that upon HSV-1 infection, cytosolic mtDNA enhanced type I interferon induction through the RNA polymerase III/RIG-I pathway. APOBEC3A was in turn induced by interferon. Deep sequencing analyses of cytosolic mtDNA mutations revealed an APOBEC3A signature predominantly in the 5'TpCpG context. These data demonstrate that upon HSV-1 infection, the mitochondrial network is disrupted, leading to the release of mtDNA and ultimately to its catabolism through APOBEC3-induced mutations. IMPORTANCE Herpes simplex virus 1 (HSV-1) impairs the mitochondrial network through the viral protein UL12.5. This leads to the fusion of mitochondria and simultaneous release of mitochondrial DNA (mtDNA) in a mouse model. We have shown that released mtDNA is recognized as a danger signal, capable of stimulating signaling pathways and inducing the production of proinflammatory cytokines. The expression of the human cytidine deaminase APOBEC3A is highly upregulated by interferon responses. This enzyme catalyzes the deamination of cytidine to uridine in single-stranded DNA substrates, resulting in the catabolism of edited DNA. Using human cell lines deprived of mtDNA and viral strains deficient in UL12, we demonstrated the implication of mtDNA in the production of interferon and APOBEC3A expression during viral infection. We have shown that HSV-1 induces mitochondrial network fragmentation in a human model and confirmed the implication of RNA polymerase III/RIG-I signaling in the capture of cytosolic mtDNA.
    Keywords:  APOBEC3A; HSV-1; cytidine deaminase; herpes simplex virus; innate immunity; mitochondria
    DOI:  https://doi.org/10.1128/mBio.02557-21
  19. Cell Rep. 2021 Nov 23. pii: S2211-1247(21)01520-5. [Epub ahead of print]37(8): 110038
    LARP7 ameliorates cellular senescence and aging by allosterically enhancing SIRT1 deacetylase activity.
    Pengyi Yan, Zixuan Li, Junhao Xiong, Zilong Geng, Weiting Wei, Yan Zhang, Gengze Wu, Tao Zhuang, Xiaoyu Tian, Zhijie Liu, Junling Liu, Kun Sun, Fengyuan Chen, Yuzhen Zhang, Chunyu Zeng, Yu Huang, Bing Zhang.
      Cellular senescence is associated with pleiotropic physiopathological processes, including aging and age-related diseases. The persistent DNA damage is a major stress leading to senescence, but the underlying molecular link remains elusive. Here, we identify La Ribonucleoprotein 7 (LARP7), a 7SK RNA binding protein, as an aging antagonist. DNA damage-mediated Ataxia Telangiectasia Mutated (ATM) activation triggers the extracellular shuttling and downregulation of LARP7, which dampens SIRT1 deacetylase activity, enhances p53 and NF-κB (p65) transcriptional activity by augmenting their acetylation, and thereby accelerates cellular senescence. Deletion of LARP7 leads to senescent cell accumulation and premature aging in rodent model. Furthermore, we show this ATM-LARP7-SIRT1-p53/p65 senescence axis is active in vascular senescence and atherogenesis, and preventing its activation substantially alleviates senescence and atherogenesis. Together, this study identifies LARP7 as a gatekeeper of senescence, and the altered ATM-LARP7-SIRT1-p53/p65 pathway plays an important role in DNA damage response (DDR)-mediated cellular senescence and atherosclerosis.
    Keywords:  DNA damage; LARP7; aging; atherosclerosis; senescence
    DOI:  https://doi.org/10.1016/j.celrep.2021.110038
  20. Trends Cell Biol. 2021 Nov 19. pii: S0962-8924(21)00221-X. [Epub ahead of print]
    Mitochondrial regulation and white adipose tissue homeostasis.
    Qingzhang Zhu, Yu A An, Philipp E Scherer.
      The important role of mitochondria in the regulation of white adipose tissue (WAT) remodeling and energy balance is increasingly appreciated. The remarkable heterogeneity of the adipose tissue stroma provides a cellular basis to enable adipose tissue plasticity in response to various metabolic stimuli. Regulating mitochondrial function at the cellular level in adipocytes, in adipose progenitor cells (APCs), and in adipose tissue macrophages (ATMs) has a profound impact on adipose homeostasis. Moreover, mitochondria facilitate the cell-to-cell communication within WAT, as well as the crosstalk with other organs, such as the liver, the heart, and the pancreas. A better understanding of mitochondrial regulation in the diverse adipose tissue cell types allows us to develop more specific and efficient approaches to improve adipose function and achieve improvements in overall metabolic health.
    DOI:  https://doi.org/10.1016/j.tcb.2021.10.008
  21. Oxid Med Cell Longev. 2021 ;2021 3960773
    Mitochondrial Quality Control in the Maintenance of Cardiovascular Homeostasis: The Roles and Interregulation of UPS, Mitochondrial Dynamics and Mitophagy.
    Yujie Song, Yuerong Xu, Yingying Liu, Jie Gao, Lele Feng, Yuxi Zhang, Lei Shi, Miao Zhang, Dong Guo, Bingchao Qi, Mingming Zhang.
      Maintenance of normal function of mitochondria is vital to the fate and health of cardiomyocytes. Mitochondrial quality control (MQC) mechanisms are essential in governing mitochondrial integrity and function. The ubiquitin-proteasome system (UPS), mitochondrial dynamics, and mitophagy are three major components of MQC. With the progress of research, our understanding of MQC mechanisms continues to deepen. Gradually, we realize that the three MQC mechanisms are not independent of each other. To the contrary, there are crosstalk among the mechanisms, which can make them interact with each other and cooperate well, forming a triangle interplay. Briefly, the UPS system can regulate the level of mitochondrial dynamic proteins and mitophagy receptors. In the process of Parkin-dependent mitophagy, the UPS is also widely activated, performing critical roles. Mitochondrial dynamics have a profound influence on mitophagy. In this review, we provide new processes of the three major MQC mechanisms in the background of cardiomyocytes and delve into the relationship between them.
    DOI:  https://doi.org/10.1155/2021/3960773
  22. Pharmaceuticals (Basel). 2021 Nov 17. pii: 1178. [Epub ahead of print]14(11):
    RIG-I Deficiency Promotes Obesity-Induced Insulin Resistance.
    Gabsik Yang, Hye Eun Lee, Jin Kyung Seok, Han Chang Kang, Yong-Yeon Cho, Hye Suk Lee, Joo Young Lee.
      Inflammation and immunity are linked to the onset and development of obesity and metabolic disorders. Pattern recognition receptors (PRRs) are key regulators of inflammation and immunity in response to infection and stress, and they have critical roles in metainflammation. In this study, we investigated whether RIG-I (retinoic acid-inducible gene I)-like receptors were involved in the regulation of obesity-induced metabolic stress in RIG-I knockout (KO) mice fed a high-fat diet (HFD). RIG-I KO mice fed an HFD for 12 weeks showed greater body weight gain, higher fat composition, lower lean body mass, and higher epididymal white adipose tissue (eWAT) weight than WT mice fed HFD. In contrast, body weight gain, fat, and lean mass compositions, and eWAT weight of MDA5 (melanoma differentiation-associated protein 5) KO mice fed HFD were similar to those of WT mice fed a normal diet. RIG-I KO mice fed HFD exhibited more severely impaired glucose tolerance and higher HOMA-IR values than WT mice fed HFD. IFN-β expression induced by ER stress inducers, tunicamycin and thapsigargin, was abolished in RIG-I-deficient hepatocytes and macrophages, showing that RIG-I is required for ER stress-induced IFN-β expression. Our results show that RIG-I deficiency promotes obesity and insulin resistance induced by a high-fat diet, presenting a novel role of RIG-I in the development of obesity and metabolic disorders.
    Keywords:  ER stress; metabolic syndrome; metainflammation; obesity; pattern-recognition receptors
    DOI:  https://doi.org/10.3390/ph14111178
  23. Genes (Basel). 2021 Oct 22. pii: 1668. [Epub ahead of print]12(11):
    Gaining Insight into Mitochondrial Genetic Variation and Downstream Pathophysiology: What Can i(PSCs) Do?
    Jesse D Moreira, Deepa M Gopal, Darrell N Kotton, Jessica L Fetterman.
      Mitochondria are specialized organelles involved in energy production that have retained their own genome throughout evolutionary history. The mitochondrial genome (mtDNA) is maternally inherited and requires coordinated regulation with nuclear genes to produce functional enzyme complexes that drive energy production. Each mitochondrion contains 5-10 copies of mtDNA and consequently, each cell has several hundreds to thousands of mtDNAs. Due to the presence of multiple copies of mtDNA in a mitochondrion, mtDNAs with different variants may co-exist, a condition called heteroplasmy. Heteroplasmic variants can be clonally expanded, even in post-mitotic cells, as replication of mtDNA is not tied to the cell-division cycle. Heteroplasmic variants can also segregate during germ cell formation, underlying the inheritance of some mitochondrial mutations. Moreover, the uneven segregation of heteroplasmic variants is thought to underlie the heterogeneity of mitochondrial variation across adult tissues and resultant differences in the clinical presentation of mitochondrial disease. Until recently, however, the mechanisms mediating the relation between mitochondrial genetic variation and disease remained a mystery, largely due to difficulties in modeling human mitochondrial genetic variation and diseases. The advent of induced pluripotent stem cells (iPSCs) and targeted gene editing of the nuclear, and more recently mitochondrial, genomes now provides the ability to dissect how genetic variation in mitochondrial genes alter cellular function across a variety of human tissue types. This review will examine the origins of mitochondrial heteroplasmic variation and propagation, and the tools used to model mitochondrial genetic diseases. Additionally, we discuss how iPSC technologies represent an opportunity to advance our understanding of human mitochondrial genetics in disease.
    Keywords:  heteroplasmy; induced pluripotent stem cells; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/genes12111668
  24. iScience. 2021 Nov 18. 103471
    Immune system cells from COVID-19 patients display compromised mitochondrial-nuclear expression co-regulation and rewiring towards glycolysis.
    Hadar Medini, Amit Zirman, Dan Mishmar.
      Mitochondria are pivotal for bioenergetics, as well as in cellular response to viral infections. Nevertheless, their role in COVID-19 was largely overlooked. Here, we analyzed available bulk RNA-seq datasets from COVID-19 patients and corresponding healthy controls (three blood datasets, N=48 healthy, 119 patients; two respiratory tract datasets, N=157 healthy, 524 patients). We found significantly reduced mtDNA gene expression in blood, but not in respiratory tract samples from patient. Next, analysis of eight single-cells RNA-seq datasets from peripheral blood mononuclear cells, nasopharyngeal samples and Broncho alveolar lavage fluid (N=1,192,243 cells), revealed significantly reduced mtDNA gene expression especially in immune system cells from patients. This associated with elevated expression of nuclear DNA-encoded OXPHOS subunits, suggesting compromised mitochondrial-nuclear co-regulation. This, together with elevated expression of ROS-response genes and glycolysis enzymes in patients, suggest rewiring towards glycolysis, thus generating beneficial conditions for SARS-CoV-2 replication. Our findings underline the centrality of mitochondrial dysfunction in COVID-19.
    Keywords:  COVID-19; RNA-seq; SARS-CoV-2; mitochondrial gene expression; mtDNA; single cells
    DOI:  https://doi.org/10.1016/j.isci.2021.103471
  25. Cells. 2021 Nov 18. pii: 3216. [Epub ahead of print]10(11):
    On the Role of the Immunoproteasome in Protein Homeostasis.
    Michael Basler, Marcus Groettrup.
      Numerous cellular processes are controlled by the proteasome, a multicatalytic protease in the cytosol and nucleus of all eukaryotic cells, through regulated protein degradation. The immunoproteasome is a special type of proteasome which is inducible under inflammatory conditions and constitutively expressed in hematopoietic cells. MECL-1 (β2i), LMP2 (β1i), and LMP7 (β5i) are the proteolytically active subunits of the immunoproteasome (IP), which is known to shape the antigenic repertoire presented on major histocompatibility complex (MHC) class I molecules. Furthermore, the immunoproteasome is involved in T cell expansion and inflammatory diseases. In recent years, targeting the immunoproteasome in cancer, autoimmune diseases, and transplantation proved to be therapeutically effective in preclinical animal models. However, the prime function of standard proteasomes and immunoproteasomes is the control of protein homeostasis in cells. To maintain protein homeostasis in cells, proteasomes remove proteins which are not properly folded, which are damaged by stress conditions such as reactive oxygen species formation, or which have to be degraded on the basis of regular protein turnover. In this review we summarize the latest insights on how the immunoproteasome influences protein homeostasis.
    Keywords:  immunoproteasome; proteasome; proteasome inhibition; protein degradation; protein homeostasis; proteotoxic stress; ubiquitin; ubiquitin–proteasome system (UPS); unfolded protein response (UPR)
    DOI:  https://doi.org/10.3390/cells10113216
  26. J Mol Biol. 2021 Nov 19. pii: S0022-2836(21)00598-2. [Epub ahead of print] 167361
    MicroRNA-101-3p Modulates Mitochondrial Metabolism via the Regulation of Complex II Assembly.
    Mark Ziemann, Sze Chern Lim, Yilin Kang, Sona Samuel, Isabel Lopez Sanchez, Michael Gantier, Diana Stojanovski, Matthew McKenzie.
      MicroRNA-101-3p (miR-101-3p) is a tumour suppressor that regulates cancer proliferation and apoptotic signalling. Loss of miR-101-3p increases the expression of the Polycomb Repressive Complex 2 (PRC2) subunit enhancer of zeste homolog 2 (EZH2), resulting in alterations to the epigenome and enhanced tumorigenesis. MiR-101-3p has also been shown to modulate various aspects of cellular metabolism, however little is known about the mechanisms involved. To investigate the metabolic pathways that are regulated by miR-101-3p, we performed transcriptome and functional analyses of osteosarcoma cells transfected with miR-101-3p. We found that miR-101-3p downregulates multiple mitochondrial processes, including oxidative phosphorylation, pyruvate metabolism, the citric acid cycle and phospholipid metabolism. We also found that miR-101-3p transfection disrupts the transcription of mitochondrial DNA (mtDNA) via the downregulation of the mitochondrial transcription initiation complex proteins TFB2M and Mic60. These alterations in transcript expression disrupt mitochondrial function, with significant decreases in both basal (54%) and maximal (67%) mitochondrial respiration rates. Native gel electrophoresis revealed that this diminished respiratory capacity was associated with reduced steady-state levels of mature succinate dehydrogenase (complex II), with a corresponding reduction of complex II enzymatic activity. Furthermore, miR-101-3p transfection reduced the expression of the SDHB subunit, with a concomitant disruption of the assembly of the SDHC subunit into mature complex II. Overall, we describe a new role for miR-101-3p as a modulator of mitochondrial metabolism via its regulation of multiple mitochondrial processes, including mtDNA transcription and complex II biogenesis.
    Keywords:  MicroRNA-101; cancer metabolism; complex II biogenesis; mtDNA transcription; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.jmb.2021.167361
  27. Arthritis Rheumatol. 2021 Nov 22.
    Impaired TFAM expression promotes mitochondrial damage to drive fibroblast activation and fibrosis in systemic sclerosis.
    Xiang Zhou, Thuong Trinh-Minh, Cuong Tran-Manh, Andreas Gießl, Christina Bergmann, Andrea-Hermina Györfi, Georg Schett, Jörg H W Distler.
      OBJECTIVES: The transcription factor TFAM is controlling the transcription of core proteins required for mitochondrial homeostasis. The aim of the current study was to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function and to evaluate the consequences for fibroblast activation.METHODS: The expression of TFAM was analyzed by immunofluorescence and Western blot. The effects of TFAM knockout were investigated in cultured fibroblasts and in bleomycin-induced skin and lung fibrosis and in TβRIact -induced skin fibrosis.
    RESULTS: The expression of TFAM was downregulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The downregulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mtDNA, accumulation of deletions in mtDNA, metabolic alterations with impaired OXPHOS and release of the mitokine GDF15. Chronic, but not acute, exposure of normal fibroblasts to TGFβ mimicked the finding in SSc fibroblasts with downregulation of TFAM and accumulation of mitochondrial damage. Downregulation of TFAM promotes fibroblast activation with upregulation of fibrosis-relevant GO-terms in RNASeq, partially in a ROS-dependent manner. Mice with fibroblast-specific knockout of TFAM are prone to fibrotic tissue remodeling with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and TβRIact-overexpression. TFAM knockout fosters SMAD3 signaling to promote fibroblast activation.
    CONCLUSIONS: Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.
    DOI:  https://doi.org/10.1002/art.42033
  28. Cells. 2021 Oct 28. pii: 2937. [Epub ahead of print]10(11):
    Hormonal Regulation of Oxidative Phosphorylation in the Brain in Health and Disease.
    Katarzyna Głombik, Jan Detka, Bogusława Budziszewska.
      The developing and adult brain is a target organ for the vast majority of hormones produced by the body, which are able to cross the blood-brain barrier and bind to their specific receptors on neurons and glial cells. Hormones ensure proper communication between the brain and the body by activating adaptive mechanisms necessary to withstand and react to changes in internal and external conditions by regulating neuronal and synaptic plasticity, neurogenesis and metabolic activity of the brain. The influence of hormones on energy metabolism and mitochondrial function in the brain has gained much attention since mitochondrial dysfunctions are observed in many different pathological conditions of the central nervous system. Moreover, excess or deficiency of hormones is associated with cell damage and loss of function in mitochondria. This review aims to expound on the impact of hormones (GLP-1, insulin, thyroid hormones, glucocorticoids) on metabolic processes in the brain with special emphasis on oxidative phosphorylation dysregulation, which may contribute to the formation of pathological changes. Since the brain concentrations of sex hormones and neurosteroids decrease with age as well as in neurodegenerative diseases, in parallel with the occurrence of mitochondrial dysfunction and the weakening of cognitive functions, their beneficial effects on oxidative phosphorylation and expression of antioxidant enzymes are also discussed.
    Keywords:  brain; hormones; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/cells10112937
  29. Gut. 2021 Nov 26. pii: gutjnl-2021-326023. [Epub ahead of print]
    Footprints of a microbial toxin from the gut microbiome to mesencephalic mitochondria.
    A Raquel Esteves, Mário F Munoz-Pinto, Daniela Nunes-Costa, Emanuel Candeias, Diana F Silva, João D Magalhães, A Raquel Pereira-Santos, I Luisa Ferreira, Susana Alarico, Igor Tiago, Nuno Empadinhas, Sandra Morais Cardoso.
      OBJECTIVE: Idiopathic Parkinson's disease (PD) is characterised by alpha-synuclein (aSyn) aggregation and death of dopaminergic neurons in the midbrain. Recent evidence posits that PD may initiate in the gut by microbes or their toxins that promote chronic gut inflammation that will ultimately impact the brain. In this work, we sought to demonstrate that the effects of the microbial toxin β-N-methylamino-L-alanine (BMAA) in the gut may trigger some PD cases, which is especially worrying as this toxin is present in certain foods but not routinely monitored by public health authorities.DESIGN: To test the hypothesis, we treated wild-type mice, primary neuronal cultures, cell lines and isolated mitochondria with BMAA, and analysed its impact on gut microbiota composition, barrier permeability, inflammation and aSyn aggregation as well as in brain inflammation, dopaminergic neuronal loss and motor behaviour. To further examine the key role of mitochondria, we also determined the specific effects of BMAA on mitochondrial function and on inflammasome activation.
    RESULTS: BMAA induced extensive depletion of segmented filamentous bacteria (SFB) that regulate gut immunity, thus triggering gut dysbiosis, immune cell migration, increased intestinal inflammation, loss of barrier integrity and caudo-rostral progression of aSyn. Additionally, BMAA induced in vitro and in vivo mitochondrial dysfunction with cardiolipin exposure and consequent activation of neuronal innate immunity. These events primed neuroinflammation, dopaminergic neuronal loss and motor deficits.
    CONCLUSION: Taken together, our results demonstrate that chronic exposure to dietary BMAA can trigger a chain of events that recapitulate the evolution of the PD pathology from the gut to the brain, which is consistent with 'gut-first' PD.
    Keywords:  gut inflammation; intestinal bacteria; intestinal barrier function; neurobiology
    DOI:  https://doi.org/10.1136/gutjnl-2021-326023
  30. Cells. 2021 Nov 13. pii: 3152. [Epub ahead of print]10(11):
    MiR 208a Regulates Mitochondrial Biogenesis in Metabolically Challenged Cardiomyocytes.
    Naveen Mekala, Jacob Kurdys, Alexis Paige Vicenzi, Leana Rose Weiler, Carmen Avramut, Edwin J Vazquez, Neli Ragina, Mariana G Rosca.
      Metabolic syndrome increases the risk for cardiovascular disease including metabolic cardiomyopathy that may progress to heart failure. The decline in mitochondrial metabolism is considered a critical pathogenic mechanism that drives this progression. Considering its cardiac specificity, we hypothesized that miR 208a regulates the bioenergetic metabolism in human cardiomyocytes exposed to metabolic challenges. We screened in silico for potential miR 208a targets focusing on mitochondrial outcomes, and we found that mRNA species for mediator complex subunit 7, mitochondrial ribosomal protein 28, stanniocalcin 1, and Sortin nexin 10 are rescued by the CRISPR deletion of miR 208a in human SV40 cardiomyocytes exposed to metabolic challenges (high glucose and high albumin-bound palmitate). These mRNAs translate into proteins that are involved in nuclear transcription, mitochondrial translation, mitochondrial integrity, and protein trafficking. MiR 208a suppression prevented the decrease in myosin heavy chain α isoform induced by the metabolic stress suggesting protection against a decrease in cardiac contractility. MiR 208a deficiency opposed the decrease in the mitochondrial biogenesis signaling pathway, mtDNA, mitochondrial markers, and respiratory properties induced by metabolic challenges. The benefit of miR 208a suppression on mitochondrial function was canceled by the reinsertion of miR 208a. In summary, miR 208a regulates mitochondrial biogenesis and function in cardiomyocytes exposed to diabetic conditions. MiR 208a may be a therapeutic target to promote mitochondrial biogenesis in chronic diseases associated with mitochondrial defects.
    Keywords:  bioenergetics; cardiomyocytes; metabolic syndrome; miR 208a; mitochondrial biogenesis
    DOI:  https://doi.org/10.3390/cells10113152
  31. Wound Repair Regen. 2021 Nov 26.
    Role of haematopoietic cell-specific protein 1-associated protein X-1 gene in lipopolysaccharide-induced apoptosis of human dermal fibroblasts.
    Mei Ning, Yanlong Li, Zhihui Chen, Pengfei Han, Xiaolan Tang, Yanli Zhang, Luan Gao.
      Wound healing may be disrupted by lipopolysaccharide (LPS)-induced mitochondrial dysfunction, inflammation, and excessive oxidative stress, which can lead to undesirable consequences. The haematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) is a mitochondrial matrix protein that regulates mitochondrial function. This study aimed to comprehensively identify the role of HAX-1 in the inhibition of LPS-induced mitochondrial dysfunction and apoptosis in human dermal fibroblasts (HDFs). HAX-1 expression was assessed in the HDF-a cell line using real-time polymerase chain reaction, western blotting, and immunohistochemical staining. The viability, migration, and apoptosis of HDF-a cells were evaluated using the water-soluble tetrazolium-1 assay, transwell assay, and flow cytometry analysis, respectively. Mitochondrial function was evaluated based on reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm). Our results demonstrated that LPS stimulation markedly repressed HAX-1 expression in HDFs and silencing of HAX-1 led to mitochondrial ROS accumulation, ΔΨm disruption, and abnormal mitochondrial morphology. Accordingly, overexpression of HAX-1 or administration of metformin enhanced mitochondrial fusion and normalized mitochondrial dynamics, thereby reversing LPS-induced mitochondrial dysfunction, fibroblast apoptosis, and viability and migration inhibition in HDF-a cells. These data support a mechanism wherein HAX-1 plays a crucial role in LPS-induced fibroblast apoptosis in a mitochondria-dependent manner.
    Keywords:  apoptosis; human dermal fibroblast; lipopolysaccharide (LPS); mitochondrial function; the haematopoietic cell-specific protein 1-associated protein X-1 (HAX-1)
    DOI:  https://doi.org/10.1111/wrr.12985
  32. Micron. 2021 Nov 12. pii: S0968-4328(21)00172-4. [Epub ahead of print]153 103181
    Molecular characteristics of proteins within the mitochondrial Fe-S cluster assembly complex.
    Tiara V Hinton, Sharon Batelu, Noah Gleason, Timothy L Stemmler.
      Iron-Sulfur (Fe-S) clusters are essential for life, as they are widely utilized in nearly every biochemical pathway. When bound to proteins, Fe-S clusters assist in catalysis, signal recognition, and energy transfer events, as well as additional cellular pathways including cellular respiration and DNA repair and replication. In Eukaryotes, Fe-S clusters are produced through coordinated activity by mitochondrial Iron-Sulfur Cluster (ISC) assembly pathway proteins through direct assembly, or through the production of the activated sulfur substrate used by the Cytosolic Iron-Sulfur Cluster Assembly (CIA) pathway. In the mitochondria, Fe-S cluster assembly is accomplished through the coordinated activity of the ISC pathway protein complex composed of a cysteine desulfurase, a scaffold protein, the accessory ISD11 protein, the acyl carrier protein, frataxin, and a ferredoxin; downstream events that accomplish Fe-S cluster transfer and delivery are driven by additional chaperone/delivery proteins that interact with the ISC assembly complex. Deficiency in human production or activity of Fe-S cluster containing proteins is often detrimental to cell and organism viability. Here we summarize what is known about the structure and functional activities of the proteins involved in the early steps of assembling [2Fe-2S] clusters before they are transferred to proteins devoted to their delivery. Our goal is to provide a comprehensive overview of how the ISC assembly apparatus proteins interact to make the Fe-S cluster which can be delivered to proteins downstream to the assembly event.
    Keywords:  Acyl carrier protein; Cysteine desulfurase; Ferredoxin; Frataxin; Friedrich’s ataxia; Iron-sulfur clusters; Scaffold
    DOI:  https://doi.org/10.1016/j.micron.2021.103181
  33. Trends Cell Biol. 2021 Nov 23. pii: S0962-8924(21)00207-5. [Epub ahead of print]
    Rewiring cell signalling pathways in pathogenic mtDNA mutations.
    Chih-Yao Chung, Gabriel E Valdebenito, Anitta R Chacko, Michael R Duchen.
      Mitochondria generate the energy to sustain cell viability and serve as a hub for cell signalling. Their own genome (mtDNA) encodes genes critical for oxidative phosphorylation. Mutations of mtDNA cause major disease and disability with a wide range of presentations and severity. We review here an emerging body of data suggesting that changes in cell metabolism and signalling pathways in response to the presence of mtDNA mutations play a key role in shaping disease presentation and progression. Understanding the impact of mtDNA mutations on cellular energy homeostasis and signalling pathways seems fundamental to identify novel therapeutic interventions with the potential to improve the prognosis for patients with primary mitochondrial disease.
    Keywords:  cell signalling; heteroplasmy; metabolic remodelling; mitochondrial disease; mtDNA
    DOI:  https://doi.org/10.1016/j.tcb.2021.10.005
  34. J Fam Pract. 2021 Oct;70(8): E1
    Let's talk about healthy aging (but where to begin?).
    John Hickner.
      
    DOI:  https://doi.org/10.12788/jfp.0282
  35. Nat Commun. 2021 Nov 25. 12(1): 6850
    Hematopoiesis under telomere attrition at the single-cell resolution.
    Natthakan Thongon, Feiyang Ma, Andrea Santoni, Matteo Marchesini, Elena Fiorini, Ashley Rose, Vera Adema, Irene Ganan-Gomez, Emma M Groarke, Fernanda Gutierrez-Rodrigues, Shuaitong Chen, Pamela Lockyer, Sarah Schneider, Carlos Bueso-Ramos, Guillermo Montalban-Bravo, Caleb A Class, Kelly A Soltysiak, Matteo Pellegrini, Ergun Sahin, Alison A Bertuch, Courtney D DiNardo, Guillermo Garcia-Manero, Neal S Young, Karen Dwyer, Simona Colla.
      The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells' self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells' skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance.
    DOI:  https://doi.org/10.1038/s41467-021-27206-7
  36. Int J Mol Sci. 2021 Nov 21. pii: 12539. [Epub ahead of print]22(22):
    How Immunosenescence and Inflammaging May Contribute to Hyperinflammatory Syndrome in COVID-19.
    Ludmila Müller, Svetlana Di Benedetto.
      Aging is characterized by the dynamic remodeling of the immune system designated "immunosenescence," and is associated with altered hematopoiesis, thymic involution, and lifelong immune stimulation by multitudinous chronic stressors, including the cytomegalovirus (CMV). Such alterations may contribute to a lowered proportion of naïve T-cells and to reduced diversity of the T-cell repertoire. In the peripheral circulation, a shift occurs towards accumulations of T and B-cell populations with memory phenotypes, and to accumulation of putatively senescent and exhausted immune cells. The aging-related accumulations of functionally exhausted memory T lymphocytes, commonly secreting pro-inflammatory cytokines, together with mediators and factors of the innate immune system, are considered to contribute to the low-grade inflammation (inflammaging) often observed in elderly people. These senescent immune cells not only secrete inflammatory mediators, but are also able to negatively modulate their environments. In this review, we give a short summary of the ways that immunosenescence, inflammaging, and CMV infection may cause insufficient immune responses, contribute to the establishment of the hyperinflammatory syndrome and impact the severity of the coronavirus disease 2019 (COVID-19) in elderly people.
    Keywords:  CMV; COVID-19; aging; cytokine storm; hyperinflammatory syndrome; immunosenescence; inflammaging; senescence-associated secretory phenotype (SASP)
    DOI:  https://doi.org/10.3390/ijms222212539
  37. Nat Immunol. 2021 Nov 22.
    Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation.
    Bowen Wu, Tuantuan V Zhao, Ke Jin, Zhaolan Hu, Matthew P Abdel, Ken J Warrington, Jörg J Goronzy, Cornelia M Weyand.
      Misdirected immunity gives rise to the autoimmune tissue inflammation of rheumatoid arthritis, in which excess production of the cytokine tumor necrosis factor (TNF) is a central pathogenic event. Mechanisms underlying the breakdown of self-tolerance are unclear, but T cells in the arthritic joint have a distinctive metabolic signature of ATPlo acetyl-CoAhi proinflammatory effector cells. Here we show that a deficiency in the production of mitochondrial aspartate is an important abnormality in these autoimmune T cells. Shortage of mitochondrial aspartate disrupted the regeneration of the metabolic cofactor nicotinamide adenine dinucleotide, causing ADP deribosylation of the endoplasmic reticulum (ER) sensor GRP78/BiP. As a result, ribosome-rich ER membranes expanded, promoting co-translational translocation and enhanced biogenesis of transmembrane TNF. ERrich T cells were the predominant TNF producers in the arthritic joint. Transfer of intact mitochondria into T cells, as well as supplementation of exogenous aspartate, rescued the mitochondria-instructed expansion of ER membranes and suppressed TNF release and rheumatoid tissue inflammation.
    DOI:  https://doi.org/10.1038/s41590-021-01065-2
  38. Nanomaterials (Basel). 2021 Nov 06. pii: 2991. [Epub ahead of print]11(11):
    The Interactions between Nanoparticles and the Innate Immune System from a Nanotechnologist Perspective.
    Lena M Ernst, Eudald Casals, Paola Italiani, Diana Boraschi, Victor Puntes.
      The immune system contributes to maintaining the body's functional integrity through its two main functions: recognizing and destroying foreign external agents (invading microorganisms) and identifying and eliminating senescent cells and damaged or abnormal endogenous entities (such as cellular debris or misfolded/degraded proteins). Accordingly, the immune system can detect molecular and cellular structures with a spatial resolution of a few nm, which allows for detecting molecular patterns expressed in a great variety of pathogens, including viral and bacterial proteins and bacterial nucleic acid sequences. Such patterns are also expressed in abnormal cells. In this context, it is expected that nanostructured materials in the size range of proteins, protein aggregates, and viruses with different molecular coatings can engage in a sophisticated interaction with the immune system. Nanoparticles can be recognized or passed undetected by the immune system. Once detected, they can be tolerated or induce defensive (inflammatory) or anti-inflammatory responses. This paper describes the different modes of interaction between nanoparticles, especially inorganic nanoparticles, and the immune system, especially the innate immune system. This perspective should help to propose a set of selection rules for nanosafety-by-design and medical nanoparticle design.
    Keywords:  immune system; inflammation; innate immunity; nanoparticles; tolerance
    DOI:  https://doi.org/10.3390/nano11112991
  39. iScience. 2021 Nov 19. 24(11): 103366
    Metabolism of cancer cells commonly responds to irradiation by a transient early mitochondrial shutdown.
    Adam Krysztofiak, Klaudia Szymonowicz, Julian Hlouschek, Kexu Xiang, Christoph Waterkamp, Safa Larafa, Isabell Goetting, Silvia Vega-Rubin-de-Celis, Carsten Theiss, Veronika Matschke, Daniel Hoffmann, Verena Jendrossek, Johann Matschke.
      Cancer bioenergetics fuel processes necessary to maintain viability and growth under stress conditions. We hypothesized that cancer metabolism supports the repair of radiation-induced DNA double-stranded breaks (DSBs). We combined the systematic collection of metabolic and radiobiological data from a panel of irradiated cancer cell lines with mathematical modeling and identified a common metabolic response with impact on the DSB repair kinetics, including a mitochondrial shutdown followed by compensatory glycolysis and resumption of mitochondrial function. Combining ionizing radiation (IR) with inhibitors of the compensatory glycolysis or mitochondrial respiratory chain slowed mitochondrial recovery and DNA repair kinetics, offering an opportunity for therapeutic intervention. Mathematical modeling allowed us to generate new hypotheses on general and individual mechanisms of the radiation response with relevance to DNA repair and on metabolic vulnerabilities induced by cancer radiotherapy. These discoveries will guide future mechanistic studies for the discovery of metabolic targets for overcoming intrinsic or therapy-induced radioresistance.
    Keywords:  Cancer; Cancer systems biology; Mathematical biosciences
    DOI:  https://doi.org/10.1016/j.isci.2021.103366
  40. Cell Rep. 2021 Nov 23. pii: S2211-1247(21)01516-3. [Epub ahead of print]37(8): 110034
    SUMO orchestrates multiple alternative DNA-protein crosslink repair pathways.
    Nataliia Serbyn, Ivona Bagdiul, Audrey Noireterre, Agnès H Michel, Raymond T Suhandynata, Huilin Zhou, Benoît Kornmann, Françoise Stutz.
      Endogenous metabolites, environmental agents, and therapeutic drugs promote formation of covalent DNA-protein crosslinks (DPCs). Persistent DPCs compromise genome integrity and are eliminated by multiple repair pathways. Aberrant Top1-DNA crosslinks, or Top1ccs, are processed by Tdp1 and Wss1 functioning in parallel pathways in Saccharomyces cerevisiae. It remains obscure how cells choose between diverse mechanisms of DPC repair. Here, we show that several SUMO biogenesis factors (Ulp1, Siz2, Slx5, and Slx8) control repair of Top1cc or an analogous DPC lesion. Genetic analysis reveals that SUMO promotes Top1cc processing in the absence of Tdp1 but has an inhibitory role if cells additionally lack Wss1. In the tdp1Δ wss1Δ mutant, the E3 SUMO ligase Siz2 stimulates sumoylation in the vicinity of the DPC, but not SUMO conjugation to Top1. This Siz2-dependent sumoylation inhibits alternative DPC repair mechanisms, including Ddi1. Our findings suggest that SUMO tunes available repair pathways to facilitate faithful DPC repair.
    Keywords:  DNA-protein crosslink; DPC repair; Flp-nick; STUbL; SUMO; Siz2; Tdp1; Top1; Top1cc; Ulp1; Wss1
    DOI:  https://doi.org/10.1016/j.celrep.2021.110034
  41. Eur Cell Mater. 2021 Nov 25. 41 401-414
    TWIST1 controls cellular senescence and energy metabolism in mesenchymal stem cells.
    C Voskamp, L A Anderson, W J Koevoet, S Barnhoorn, P G Mastroberardino, G J van Osch, R Narcisi.
      Mesenchymal stem cells (MSCs) are promising cells for regenerative medicine therapies because they can differentiate towards multiple cell lineages. However, the occurrence of cellular senescence and the acquiring of the senescence-associated secretory phenotype (SASP) limit their clinical use. Since the transcription factor TWIST1 influences expansion of MSCs, its role in regulating cellular senescence was investigated. The present study demonstrated that silencing of TWIST1 in MSCs increased the occurrence of senescence, characterised by a SASP profile different from irradiation-induced senescent MSCs. Knowing that senescence alters cellular metabolism, cellular bioenergetics was monitored by using the Seahorse XF apparatus. Both TWIST1-silencing-induced and irradiation-induced senescent MSCs had a higher oxygen consumption rate compared to control MSCs, while TWIST1-silencing-induced senescent MSCs had a low extracellular acidification rate compared to irradiation-induced senescent MSCs. Overall, data indicated how TWIST1 regulation influenced senescence in MSCs and that TWIST1 silencing-induced senescence was characterised by a specific SASP profile and metabolic state.
    DOI:  https://doi.org/10.22203/eCM.v042a25
  42. J Periodontal Res. 2021 Nov 26.
    Abnormal mitochondrial structure and function are retained in gingival tissues and human gingival fibroblasts from patients with chronic periodontitis.
    Jia Liu, Xiaoxuan Wang, Fei Xue, Ming Zheng, Qingxian Luan.
      BACKGROUND AND OBJECTIVE: The abnormal structure and function of mitochondria in cells is closely associated with inflammatory diseases. However, the physiology of mitochondria within gingival tissues and human gingival fibroblasts (HGFs) in patients with chronic periodontitis (CP) remains unclear. The objective of this study was to investigate the structure profile and function of mitochondria in gingival tissues and in HGFs derived from patients with or without CP. These features of mitochondria in HGFs were further analyzed when HGFs were induced by lipopolysaccharide (LPS) from Porphyromonas gingivalis (P.g).METHODS: Gingival tissues and HGFs were collected from CP and healthy patients. Mitochondrial structure was assessed by transmission electron microscopy. Tissues or cells lysis was performed for mitochondrial DNA (mtDNA) quantification, and real-time polymerase chain reaction (RT-PCR) tests were used to determine mtDNA copy numbers. Western blot analysis was used to evaluate autophagy-related protein (ATG)-5, microtubule-associated protein light chain 3 (LC3), and mitochondrial matrix protein pyruvate dehydrogenase kinase isozyme 2 (PDK2) levels in tissues and HGFs from CP and healthy individuals.
    RESULTS: Tissues and HGFs from CP showed a significant greater mitochondrial structure destruction, lower mtDNA level, increased ATG5, LC3-II, and lower PDK2 protein levels than those of healthy individuals. In addition, LPS from P.g also triggered the same results in HGFs from healthy donors. Moreover, the challenge of HGFs from CP with LPS worsened these parameters.
    CONCLUSION: Mitochondrial structure and function within gingival tissues and HGFs from CP individuals were abnormal compared to those from healthy donors, and LPS could promote mitochondrial destruction.
    Keywords:  chronic periodontitis; connective tissue; fibroblast(s); in vitro model; inflammation
    DOI:  https://doi.org/10.1111/jre.12941
  43. J Biol Chem. 2021 Nov 19. pii: S0021-9258(21)01244-8. [Epub ahead of print] 101435
    A redox cycle with complex II prioritizes sulfide quinone oxidoreductase dependent H2S oxidation.
    Roshan Kumar, Aaron P Landry, Arkajit Guha, Victor Vitvitsky, Ho Joon Lee, Keisuke Seike, Pavan Reddy, Costas A Lyssiotis, Ruma Banerjee.
      The dual roles of H2S as an endogenously synthesized respiratory substrate and as a toxin, raise questions as to how it is cleared when the electron transport chain is inhibited. Sulfide quinone oxidoreductase (SQOR) catalyzes the first step in the mitochondrial H2S oxidation pathway, using CoQ as an electron acceptor, and connects to the electron transport chain at the level of complex III. We have discovered that at high H2S concentrations, which are known to inhibit complex IV, a new redox cycle is established between SQOR and complex II, operating in reverse. Under these conditions, the purine nucleotide cycle and the malate aspartate shuttle furnish fumarate, which supports complex II reversal and leads to succinate accumulation. Complex II knockdown in colonocytes decreases the efficiency of H2S clearance while targeted knockout of complex II in intestinal epithelial cells significantly decreases the levels of thiosulfate, a biomarker of H2S oxidation, to approximately one third of the values seen in serum and urine samples from control mice. These data establish the physiological relevance of this newly discovered redox circuitry between SQOR and complex II for prioritizing H2S oxidation and reveal the quantitatively significant contribution of intestinal epithelial cells to systemic H2S metabolism.
    Keywords:  SDHA; coenzyme Q; complex II; electron transport chain; fumarate; hydrogen sulfide
    DOI:  https://doi.org/10.1016/j.jbc.2021.101435
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