bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023–07–16
fourteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression.
  2. Immunoproteasome-specific subunit PSMB9 induction is required to regulate cellular proteostasis upon mitochondrial dysfunction.
  3. Three-dimensional images reveal the impact of the endosymbiont Midichloria mitochondrii on the host mitochondria.
  4. Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion.
  5. Local coordination of mRNA storage and degradation near mitochondria modulates C. elegans ageing.
  6. Loss of STING in parkin mutant flies suppresses muscle defects and mitochondria damage.
  7. Increased mitochondrial free Ca2+ during ischemia is suppressed, but not eliminated by, germline deletion of the mitochondrial Ca2+ uniporter.
  8. Mitofusin-2 in nucleus accumbens D2-MSNs regulates social dominance and neuronal function.
  9. Deciphering the mitophagy receptor network identifies a crucial role for OPTN (optineurin) in acute myeloid leukemia.
  10. Tethering ATG16L1 or LC3 induces targeted autophagic degradation of protein aggregates and mitochondria.
  11. IP3R at ER-Mitochondrial Contact Sites: Beyond the IP3R-GRP75-VDAC1 Ca2+ Funnel.
  12. Manipulating mitochondrial dynamics in the NTS prevents diet-induced deficits in brown fat morphology and glucose uptake.
  13. Chasing the right tail: How the ER membrane complex recognizes its substrates.
  14. Mitochondria as intracellular signalling organelles. An update.
  1. EMBO J. 2023 Jul 13. e113256
    Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression.
    Nils Grotehans, Lynn McGarry, Hendrik Nolte, Vanessa Xavier, Moritz Kroker, Álvaro Jesús Narbona-Pérez, Soni Deshwal, Patrick Giavalisco, Thomas Langer, Thomas MacVicar.
      Replication of the mitochondrial genome and expression of the genes it encodes both depend on a sufficient supply of nucleotides to mitochondria. Accordingly, dysregulated nucleotide metabolism not only destabilises the mitochondrial genome, but also affects its transcription. Here, we report that a mitochondrial nucleoside diphosphate kinase, NME6, supplies mitochondria with pyrimidine ribonucleotides that are necessary for the transcription of mitochondrial genes. Loss of NME6 function leads to the depletion of mitochondrial transcripts, as well as destabilisation of the electron transport chain and impaired oxidative phosphorylation. These deficiencies are rescued by an exogenous supply of pyrimidine ribonucleosides. Moreover, NME6 is required for the maintenance of mitochondrial DNA when the access to cytosolic pyrimidine deoxyribonucleotides is limited. Our results therefore reveal an important role for ribonucleotide salvage in mitochondrial gene expression.
    Keywords:  NME6; mitochondria; mitochondrial DNA; mitochondrial transcription; nucleotide metabolism
    DOI:  https://doi.org/10.15252/embj.2022113256
  2. Nat Commun. 2023 07 11. 14(1): 4092
    Immunoproteasome-specific subunit PSMB9 induction is required to regulate cellular proteostasis upon mitochondrial dysfunction.
    Minji Kim, Remigiusz A Serwa, Lukasz Samluk, Ida Suppanz, Agata Kodroń, Tomasz M Stępkowski, Praveenraj Elancheliyan, Biniyam Tsegaye, Silke Oeljeklaus, Michal Wasilewski, Bettina Warscheid, Agnieszka Chacinska.
      Perturbed cellular protein homeostasis (proteostasis) and mitochondrial dysfunction play an important role in neurodegenerative diseases, however, the interplay between these two phenomena remains unclear. Mitochondrial dysfunction leads to a delay in mitochondrial protein import, causing accumulation of non-imported mitochondrial proteins in the cytosol and challenging proteostasis. Cells respond by increasing proteasome activity and molecular chaperones in yeast and C. elegans. Here, we demonstrate that in human cells mitochondrial dysfunction leads to the upregulation of a chaperone HSPB1 and, interestingly, an immunoproteasome-specific subunit PSMB9. Moreover, PSMB9 expression is dependent on the translation elongation factor EEF1A2. These mechanisms constitute a defense response to preserve cellular proteostasis under mitochondrial stress. Our findings define a mode of proteasomal activation through the change in proteasome composition driven by EEF1A2 and its spatial regulation, and are useful to formulate therapies to prevent neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41467-023-39642-8
  3. Nat Commun. 2023 07 12. 14(1): 4133
    Three-dimensional images reveal the impact of the endosymbiont Midichloria mitochondrii on the host mitochondria.
    Zerrin Uzum, Dmitry Ershov, Michael J Pavia, Adeline Mallet, Olivier Gorgette, Olivier Plantard, Davide Sassera, Fabrizia Stavru.
      The hard tick, Ixodes ricinus, a main Lyme disease vector, harbors an intracellular bacterial endosymbiont. Midichloria mitochondrii is maternally inherited and resides in the mitochondria of I. ricinus oocytes, but the consequences of this endosymbiosis are not well understood. Here, we provide 3D images of wild-type and aposymbiotic I. ricinus oocytes generated with focused ion beam-scanning electron microscopy. Quantitative image analyses of endosymbionts and oocyte mitochondria at different maturation stages show that the populations of both mitochondrion-associated bacteria and bacterium-hosting mitochondria increase upon vitellogenisation, and that mitochondria can host multiple bacteria in later stages. Three-dimensional reconstructions show symbiosis-dependent morphologies of mitochondria and demonstrate complete M. mitochondrii inclusion inside a mitochondrion. Cytoplasmic endosymbiont located close to mitochondria are not oriented towards the mitochondria, suggesting that bacterial recolonization is unlikely. We further demonstrate individual globular-shaped mitochondria in the wild type oocytes, while aposymbiotic oocytes only contain a mitochondrial network. In summary, our study suggests that M. mitochondrii modulates mitochondrial fragmentation in oogenesis possibly affecting organelle function and ensuring its presence over generations.
    DOI:  https://doi.org/10.1038/s41467-023-39758-x
  4. Nat Commun. 2023 07 11. 14(1): 4105
    Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion.
    Tianshu Hao, Jianglong Yu, Zhida Wu, Jie Jiang, Longlong Gong, Bingjun Wang, Hanze Guo, Huabin Zhao, Bin Lu, Simone Engelender, He He, Zhiyin Song.
      Mitochondria are the key organelles for sensing oxygen, which is consumed by oxidative phosphorylation to generate ATP. Lysosomes contain hydrolytic enzymes that degrade misfolded proteins and damaged organelles to maintain cellular homeostasis. Mitochondria physically and functionally interact with lysosomes to regulate cellular metabolism. However, the mode and biological functions of mitochondria-lysosome communication remain largely unknown. Here, we show that hypoxia remodels normal tubular mitochondria into megamitochondria by inducing broad inter-mitochondria contacts and subsequent fusion. Importantly, under hypoxia, mitochondria-lysosome contacts are promoted, and certain lysosomes are engulfed by megamitochondria, in a process we term megamitochondria engulfing lysosome (MMEL). Both megamitochondria and mature lysosomes are required for MMEL. Moreover, the STX17-SNAP29-VAMP7 complex contributes to mitochondria-lysosome contacts and MMEL under hypoxia. Intriguingly, MMEL mediates a mode of mitochondrial degradation, which we termed mitochondrial self-digestion (MSD). Moreover, MSD increases mitochondrial ROS production. Our results reveal a mode of crosstalk between mitochondria and lysosomes and uncover an additional pathway for mitochondrial degradation.
    DOI:  https://doi.org/10.1038/s41467-023-39811-9
  5. EMBO J. 2023 Jul 10. e112446
    Local coordination of mRNA storage and degradation near mitochondria modulates C. elegans ageing.
    Ioanna Daskalaki, Maria Markaki, Ilias Gkikas, Nektarios Tavernarakis.
      Mitochondria are central regulators of healthspan and lifespan, yet the intricate choreography of multiple, tightly controlled steps regulating mitochondrial biogenesis remains poorly understood. Here, we uncover a pivotal role for specific elements of the 5'-3' mRNA degradation pathway in the regulation of mitochondrial abundance and function. We find that the mRNA degradation and the poly-A tail deadenylase CCR4-NOT complexes form distinct foci in somatic Caenorhabditis elegans cells that physically and functionally associate with mitochondria. Components of these two multi-subunit complexes bind transcripts of nuclear-encoded mitochondria-targeted proteins to regulate mitochondrial biogenesis during ageing in an opposite manner. In addition, we show that balanced degradation and storage of mitochondria-targeted protein mRNAs are critical for mitochondrial homeostasis, stress resistance and longevity. Our findings reveal a multifaceted role of mRNA metabolism in mitochondrial biogenesis and show that fine-tuning of mRNA turnover and local translation control mitochondrial abundance and promote longevity in response to stress and during ageing.
    Keywords:  ageing; mRNA metabolism; mitochondria; protein synthesis; stress
    DOI:  https://doi.org/10.15252/embj.2022112446
  6. PLoS Genet. 2023 Jul 13. 19(7): e1010828
    Loss of STING in parkin mutant flies suppresses muscle defects and mitochondria damage.
    Andrew T Moehlman, Gil Kanfer, Richard J Youle.
      The early pathogenesis and underlying molecular causes of motor neuron degeneration in Parkinson's Disease (PD) remains unresolved. In the model organism Drosophila melanogaster, loss of the early-onset PD gene parkin (the ortholog of human PRKN) results in impaired climbing ability, damage to the indirect flight muscles, and mitochondrial fragmentation with swelling. These stressed mitochondria have been proposed to activate innate immune pathways through release of damage associated molecular patterns (DAMPs). Parkin-mediated mitophagy is hypothesized to suppress mitochondrial damage and subsequent activation of the cGAS/STING innate immunity pathway, but the relevance of this interaction in the fly remains unresolved. Using a combination of genetics, immunoassays, and RNA sequencing, we investigated a potential role for STING in the onset of parkin-null phenotypes. Our findings demonstrate that loss of Drosophila STING in flies rescues the thorax muscle defects and the climbing ability of parkin-/- mutants. Loss of STING also suppresses the disrupted mitochondrial morphology in parkin-/- flight muscles, suggesting unexpected feedback of STING on mitochondria integrity or activation of a compensatory mitochondrial pathway. In the animals lacking both parkin and sting, PINK1 is activated and cell death pathways are suppressed. These findings support a unique, non-canonical role for Drosophila STING in the cellular and organismal response to mitochondria stress.
    DOI:  https://doi.org/10.1371/journal.pgen.1010828
  7. Cell Rep. 2023 Jul 07. pii: S2211-1247(23)00746-5. [Epub ahead of print]42(7): 112735
    Increased mitochondrial free Ca2+ during ischemia is suppressed, but not eliminated by, germline deletion of the mitochondrial Ca2+ uniporter.
    Courtney E Petersen, Junhui Sun, Kavisha Silva, Anna Kosmach, Robert S Balaban, Elizabeth Murphy.
      Mitochondrial Ca2+ overload is proposed to regulate cell death via opening of the mitochondrial permeability transition pore. It is hypothesized that inhibition of the mitochondrial Ca2+ uniporter (MCU) will prevent Ca2+ accumulation during ischemia/reperfusion and thereby reduce cell death. To address this, we evaluate mitochondrial Ca2+ in ex-vivo-perfused hearts from germline MCU-knockout (KO) and wild-type (WT) mice using transmural spectroscopy. Matrix Ca2+ levels are measured with a genetically encoded, red fluorescent Ca2+ indicator (R-GECO1) using an adeno-associated viral vector (AAV9) for delivery. Due to the pH sensitivity of R-GECO1 and the known fall in pH during ischemia, hearts are glycogen depleted to decrease the ischemic fall in pH. At 20 min of ischemia, there is significantly less mitochondrial Ca2+ in MCU-KO hearts compared with MCU-WT controls. However, an increase in mitochondrial Ca2+ is present in MCU-KO hearts, suggesting that mitochondrial Ca2+ overload during ischemia is not solely dependent on MCU.
    Keywords:  CP: Developmental biology; MCU; calcium; cardioprotection; ischemia-reperfusion; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2023.112735
  8. Cell Rep. 2023 Jul 11. pii: S2211-1247(23)00787-8. [Epub ahead of print]42(7): 112776
    Mitofusin-2 in nucleus accumbens D2-MSNs regulates social dominance and neuronal function.
    Sriparna Ghosal, Elias Gebara, Eva Ramos-Fernández, Alessandro Chioino, Jocelyn Grosse, Isabelle Guillot de Suduiraut, Olivia Zanoletti, Bernard Schneider, Antonio Zorzano, Simone Astori, Carmen Sandi.
      The nucleus accumbens (NAc) is a brain hub regulating motivated behaviors, including social competitiveness. Mitochondrial function in the NAc links anxiety with social competitiveness, and the mitochondrial fusion protein mitofusin 2 (Mfn2) in NAc neurons regulates anxiety-related behaviors. However, it remains unexplored whether accumbal Mfn2 levels also affect social behavior and whether Mfn2 actions in the emotional and social domain are driven by distinct cell types. Here, we found that subordinate-prone highly anxious rats show decreased accumbal Mfn2 levels and that Mfn2 overexpression promotes dominant behavior. In mice, selective Mfn2 downregulation in NAc dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) induced social subordination, accompanied by decreased accumbal mitochondrial functions and decreased excitability in D2-MSNs. Instead, D1-MSN-targeted Mfn2 downregulation affected competitive ability only transiently and likely because of an increase in anxiety-like behaviors. Our results assign dissociable cell-type specific roles to Mfn2 in the NAc in modulating social dominance and anxiety.
    Keywords:  CP: Neuroscience; anxiety; medium spiny neurons; mitochondria; mitofusin 2; motivation; nucleus accumbens; social competition; social dominance; tube test
    DOI:  https://doi.org/10.1016/j.celrep.2023.112776
  9. Autophagy. 2023 Jul 13. 1-15
    Deciphering the mitophagy receptor network identifies a crucial role for OPTN (optineurin) in acute myeloid leukemia.
    Laura M Meyer, Sebastian E Koschade, Jonas B Vischedyk, Marlyn Thoelken, Andrea Gubas, Martin Wegner, Marion Basoglu, Stefan Knapp, Manuel Kaulich, Stefan Eimer, Shabnam Shaid, Christian H Brandts.
      The selective autophagic degradation of mitochondria via mitophagy is essential for preserving mitochondrial homeostasis and, thereby, disease maintenance and progression in acute myeloid leukemia (AML). Mitophagy is orchestrated by a variety of mitophagy receptors whose interplay is not well understood. Here, we established a pairwise multiplexed CRISPR screen targeting mitophagy receptors to elucidate redundancies and gain a deeper understanding of the functional interactome governing mitophagy in AML. We identified OPTN (optineurin) as sole non-redundant mitophagy receptor and characterized its unique role in AML. Knockdown and overexpression experiments demonstrated that OPTN expression is rate-limiting for AML cell proliferation. In a MN1-driven murine transplantation model, loss of OPTN prolonged overall median survival by 7 days (+21%). Mechanistically, we found broadly impaired mitochondrial respiration and function with increased mitochondrial ROS, that most likely caused the proliferation defect. Our results decipher the intertwined network of mitophagy receptors in AML for both ubiquitin-dependent and receptor-mediated mitophagy, identify OPTN as a non-redundant tool to study mitophagy in the context of leukemia and suggest OPTN inhibition as an attractive therapeutic strategy.Abbreviations: AML: acute myeloid leukemia; CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats; CTRL: control; DFP: deferiprone; GI: genetic interaction; KD: knockdown; KO: knockout; ldMBM, lineage-depleted murine bone marrow; LFC: log2 fold change; LIR: LC3-interacting region; LSC: leukemic stem cell; MAGeCK: Model-based Analysis of Genome-wide CRISPR-Cas9 Knockout; MDIVI-1: mitochondrial division inhibitor 1; MOI: multiplicity of infection; MOM: mitochondrial outer membrane; NAC: N-acetyl-L-cysteine; OA: oligomycin-antimycin A; OCR: oxygen consumption rate; OE: overexpression; OPTN: optineurin; PINK1: PTEN induced putative kinase 1; ROS: reactive oxygen species; SEM: standard error of the mean; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; UBD: ubiquitin-binding domain; WT: wild type.
    Keywords:  AML; MN1-driven mouse model; Mitochondrial ROS; Multiplex CRISPR screen; genetic interactions; leukemia
    DOI:  https://doi.org/10.1080/15548627.2023.2230839
  10. Autophagy. 2023 Jul 13. 1-17
    Tethering ATG16L1 or LC3 induces targeted autophagic degradation of protein aggregates and mitochondria.
    Ligang Mei, Xiaorong Chen, Fujing Wei, Xue Huang, Lu Liu, Jia Yao, Jing Chen, Xunguang Luo, Zhuolin Wang, Aimin Yang.
      Proteolysis-targeting chimeras (PROTACs) based on the ubiquitin-proteasome system have made great progress in the field of drug discovery. There is mounting evidence that the accumulation of aggregation-prone proteins or malfunctioning organelles is associated with the occurrence of various age-related neurodegenerative disorders and cancers. However, PROTACs are inefficient for the degradation of such large targets due to the narrow entrance channel of the proteasome. Macroautophagy (hereafter referred to as autophagy) is known as a self-degradative process involved in the degradation of bulk cytoplasmic components or specific cargoes that are sequestered into autophagosomes. In the present study, we report the development of a generalizable strategy for the targeted degradation of large targets. Our results suggested that tethering large target models to phagophore-associated ATG16L1 or LC3 induced targeted autophagic degradation of the large target models. Furthermore, we successfully applied this autophagy-targeting degradation strategy to the targeted degradation of HTT65Q aggregates and mitochondria. Specifically, chimeras consisting of polyQ-binding peptide 1 (QBP) and ATG16L1-binding peptide (ABP) or LC3-interacting region (LIR) induced targeted autophagic degradation of pathogenic HTT65Q aggregates; and the chimeras consisting of mitochondria-targeting sequence (MTS) and ABP or LIR promoted targeted autophagic degradation of dysfunctional mitochondria, hence ameliorating mitochondrial dysfunction in a Parkinson disease cell model and protecting cells from apoptosis induced by the mitochondrial stress agent FCCP. Therefore, this study provides a new strategy for the selective proteolysis of large targets and enrich the toolkit for autophagy-targeting degradation.Abbreviations: ABP: ATG16L1-binding peptide; ATG16L1: autophagy related 16 like 1; ATTEC: autophagy-tethering compound; AUTAC: autophagy-targeting chimera; AUTOTAC: autophagy-targeting chimera; Baf A1: bafilomycin A1; BCL2: BCL2 apoptosis regulator; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CASP3: caspase 3; CPP: cell-penetrating peptide; CQ: chloroquine phosphate; DAPI: 4',6-diamidino-2-phenylindole; DCM: dichloromethane; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; EBSS: Earle's balanced salt solution; FCCP: carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; FITC: fluorescein-5-isothiocyanate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HEK293: human embryonic kidney 293; HEK293T: human embryonic kidney 293T; HPLC: high-performance liquid chromatography; HRP: horseradish peroxidase; HTT: huntingtin; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFF: mitochondrial fission factor; MTS: mitochondria-targeting sequence; NBR1: NBR1 autophagy cargo receptor; NLRX1: NLR family member X1; OPTN: optineurin; P2A: self-cleaving 2A peptide; PB1: Phox and Bem1p; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; PROTACs: proteolysis-targeting chimeras; QBP: polyQ-binding peptide 1; SBP: streptavidin-binding peptide; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SPATA33: spermatogenesis associated 33; TIMM23: translocase of inner mitochondrial membrane 23; TMEM59: transmembrane protein 59; TOMM20: translocase of outer mitochondrial membrane 20; UBA: ubiquitin-associated; WT: wild type.
    Keywords:  ATG16L1; HTT65Q aggregates; LC3; autophagy-targeting degradation; mitochondria; proteolysis-targeting chimeras
    DOI:  https://doi.org/10.1080/15548627.2023.2234797
  11. Contact (Thousand Oaks). 2023 Jan-Dec;6:6 25152564231181020
    IP3R at ER-Mitochondrial Contact Sites: Beyond the IP3R-GRP75-VDAC1 Ca2+ Funnel.
    Peace Atakpa-Adaji, Adelina Ivanova.
      Membrane contact sites (MCS) circumvent the topological constraints of functional coupling between different membrane-bound organelles by providing a means of communication and exchange of materials. One of the most characterised contact sites in the cell is that between the endoplasmic reticulum and the mitochondrial (ERMCS) whose function is to couple cellular Ca2+ homeostasis and mitochondrial function. Inositol 1,4,5-trisphosphate receptors (IP3Rs) on the ER, glucose-regulated protein 75 (GRP 75) and voltage-dependent anion channel 1 (VDAC1) on the outer mitochondrial membrane are the canonical component of the Ca2+ transfer unit at ERMCS. These are often reported to form a Ca2+ funnel that fuels the mitochondrial low-affinity Ca2+ uptake system. We assess the available evidence on the IP3R subtype selectivity at the ERMCS and consider if IP3Rs have other roles at the ERMCS beyond providing Ca2+. Growing evidence suggests that all three IP3R subtypes can localise and regulate Ca2+ signalling at ERMCS. Furthermore, IP3Rs may be structurally important for assembly of the ERMCS in addition to their role in providing Ca2+ at these sites. Evidence that various binding partners regulate the assembly and Ca2+ transfer at ERMCS populated by IP3R-GRP75-VDAC1, suggesting that cells have evolved mechanisms that stabilise these junctions forming a Ca2+ microdomain that is required to fuel mitochondrial Ca2+ uptake.
    Keywords:  Ca2+; GRP75; IP3 receptor; VDAC1; endoplasmic reticulum; membrane contact sites; mitochondria
    DOI:  https://doi.org/10.1177/25152564231181020
  12. Life Sci. 2023 Jul 07. pii: S0024-3205(23)00557-X. [Epub ahead of print] 121922
    Manipulating mitochondrial dynamics in the NTS prevents diet-induced deficits in brown fat morphology and glucose uptake.
    Arianna Fozzato, Lauryn E New, Joanne C Griffiths, Bianca Patel, Susan A Deuchars, Beatrice M Filippi.
       AIMS: Brown adipose tissue (BAT) can produce heat by metabolizing glucose and fatty acids. Activation of BAT is controlled by the central nervous system (CNS) through sympathetic innervation. Dysregulation of signalling molecules in selective CNS areas such as the nucleus of tractus solitarius (NTS) are linked with altered BAT activity, obesity and diabetes. High-fat diet (HFD)-feeding increases mitochondrial fragmentation in the NTS, triggering insulin resistance, hyperphagia and weight gain. Here we sought to determine whether changes in mitochondrial dynamics in the NTS can affect BAT glucose uptake.
    MAIN METHODS: Rats received DVC stereotactic surgery for local brain administration of viruses that express mutated Drp1 genes. BAT glucose uptake was measured with PET/CT scans. Biochemical assays and immunohistochemistry determined altered levels of key signalling molecules and neural innervation of BAT.
    KEY FINDINGS: We show that short-term HFD-feeding decreases BAT glucose uptake. However, inhibiting mitochondrial fragmentation in NTS-astrocytes of HFD-fed rats partially restores BAT glucose uptake accompanied by lower blood glucose and insulin levels. Tyrosine Hydroxylase (TH) revealed that rats with inhibited mitochondrial fragmentation in NTS astrocytes had higher levels of catecholaminergic innervation in BAT compared to HFD-fed rats, and did not exhibit HFD-dependent infiltration of enlarged white fat droplets in the BAT. In regular chow-fed rats, increasing mitochondrial fragmentation in the NTS-astrocytes reduced BAT glucose uptake, TH immune-positive boutons and β3-adrenergic receptor levels.
    SIGNIFICANCE: Our data suggest that targeting mitochondrial dynamics in the NTS-astrocytes could be a beneficial strategy to increase glucose utilization and protect from developing obesity and diabetes.
    Keywords:  Astrocytes; Brown adipose tissue (BAT); Insulin resistance; Mitochondria fission and fusion; Nucleus of the solitary tract (NTS); β-adrenergic stimulation
    DOI:  https://doi.org/10.1016/j.lfs.2023.121922
  13. J Cell Biol. 2023 08 07. pii: e202306035. [Epub ahead of print]222(8):
    Chasing the right tail: How the ER membrane complex recognizes its substrates.
    Doron Rapaport, Johannes M Herrmann.
      Tail-anchored proteins are tethered to membranes of the ER, mitochondria, and peroxisomes. In this issue, Pleiner and colleagues (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202212007) show that the ER membrane complex (EMC) uses an inbuilt charge-dependent selectivity filter to specifically insert ER tail-anchored proteins according to their topology signals and to prevent the misincorporation of mitochondrial proteins.
    DOI:  https://doi.org/10.1083/jcb.202306035
  14. Cell Signal. 2023 Jul 06. pii: S0898-6568(23)00208-5. [Epub ahead of print]109 110794
    Mitochondria as intracellular signalling organelles. An update.
    Lucia-Doina Popov.
      Traditionally, mitochondria are known as "the powerhouse of the cell," responsible for energy (ATP) generation (by the electron transport chain, oxidative phosphorylation, the tricarboxylic acid cycle, and fatty acid ß-oxidation), and for the regulation of several metabolic processes, including redox homeostasis, calcium signalling, and cellular apoptosis. The extensive studies conducted in the last decades portray mitochondria as multifaceted signalling organelles that ultimately command cells' survival or death. Based on current knowledge, we'll outline the mitochondrial signalling to other intracellular compartments in homeostasis and pathology-related mitochondrial stress conditions here. The following topics are discussed: (i) oxidative stress and mtROS signalling in mitohormesis, (ii) mitochondrial Ca2+ signalling; (iii) the anterograde (nucleus-to-mitochondria) and retrograde (mitochondria-to-nucleus) signal transduction, (iv) the mtDNA role in immunity and inflammation, (v) the induction of mitophagy- and apoptosis - signalling cascades, (vi) the mitochondrial dysfunctions (mitochondriopathies) in cardiovascular, neurodegenerative, and malignant diseases. The novel insights into molecular mechanisms of mitochondria-mediated signalling can explain mitochondria adaptation to metabolic and environmental stresses to achieve cell survival.
    Keywords:  Mitochondriopathies; Mitophagy; Oxidative stress; Signal transduction; mtDNA
    DOI:  https://doi.org/10.1016/j.cellsig.2023.110794
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