bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024–07–07
fiveteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. The germline coordinates mitokine signaling.
  2. Primary cilia formation requires the Leigh syndrome-associated mitochondrial protein NDUFAF2.
  3. GTPBP8 plays a role in mitoribosome formation in human mitochondria.
  4. Asymmetric apical domain states of mitochondrial Hsp60 coordinate substrate engagement and chaperonin assembly.
  5. Mitochondrial genetics through the lens of single-cell multi-omics.
  6. Functional multi-organelle units control inflammatory lipid metabolism of macrophages.
  7. Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity.
  8. Protocol for detecting mitochondria extracellular vesicles of brown adipose tissue in mice.
  9. Prohibitins, Phb1 and Phb2, function as Atg8 receptors to support yeast mitophagy and also play a negative regulatory role in Atg32 processing.
  10. Fit for purpose: Selecting the best mitochondrial DNA for the job.
  11. A mitochondrial checkpoint to NF-κB signaling.
  12. Bridging lipid metabolism and mitochondrial genome maintenance.
  13. Trafficking of mitochondrial double-stranded RNA from mitochondria to the cytosol.
  14. From whence it came: Mitochondrial mRNA leaves, a protein returns.
  15. Beyond fission and fusion-Diving into the mysteries of mitochondrial shape.
  1. Cell. 2024 Jun 26. pii: S0092-8674(24)00650-0. [Epub ahead of print]
    The germline coordinates mitokine signaling.
    Koning Shen, Jenni Durieux, Cesar G Mena, Brant M Webster, C Kimberly Tsui, Hanlin Zhang, Larry Joe, Kristen M Berendzen, Andrew Dillin.
      The ability of mitochondria to coordinate stress responses across tissues is critical for health. In C. elegans, neurons experiencing mitochondrial stress elicit an inter-tissue signaling pathway through the release of mitokine signals, such as serotonin or the Wnt ligand EGL-20, which activate the mitochondrial unfolded protein response (UPRMT) in the periphery to promote organismal health and lifespan. We find that germline mitochondria play a surprising role in neuron-to-periphery UPRMT signaling. Specifically, we find that germline mitochondria signal downstream of neuronal mitokines, Wnt and serotonin, and upstream of lipid metabolic pathways in the periphery to regulate UPRMT activation. We also find that the germline tissue itself is essential for UPRMT signaling. We propose that the germline has a central signaling role in coordinating mitochondrial stress responses across tissues, and germline mitochondria play a defining role in this coordination because of their inherent roles in germline integrity and inter-tissue signaling.
    Keywords:  C. elegans; aging; germline; lipids; mitochondria; mtUPR; proteostasis; stress response
    DOI:  https://doi.org/10.1016/j.cell.2024.06.010
  2. J Clin Invest. 2024 Jul 01. pii: e175560. [Epub ahead of print]134(13):
    Primary cilia formation requires the Leigh syndrome-associated mitochondrial protein NDUFAF2.
    Chien-Hui Lo, Zhiquan Liu, Siyu Chen, Frank Lin, Andrew R Berneshawi, Charles Q Yu, Euna B Koo, Tia J Kowal, Ke Ning, Yang Hu, Won-Jing Wang, Y Joyce Liao, Yang Sun.
      Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.
    Keywords:  Cell biology; Neurodegeneration; Neurological disorders; Ophthalmology; Retinopathy
    DOI:  https://doi.org/10.1172/JCI175560
  3. Nat Commun. 2024 Jul 05. 15(1): 5664
    GTPBP8 plays a role in mitoribosome formation in human mitochondria.
    Miriam Cipullo, Genís Valentín Gesé, Shreekara Gopalakrishna, Annika Krueger, Vivian Lobo, Maria A Pirozhkova, James Marks, Petra Páleníková, Dmitrii Shiriaev, Yong Liu, Jelena Misic, Yu Cai, Minh Duc Nguyen, Abubakar Abdelbagi, Xinping Li, Michal Minczuk, Markus Hafner, Daniel Benhalevy, Aishe A Sarshad, Ilian Atanassov, B Martin Hällberg, Joanna Rorbach.
      Mitochondrial gene expression relies on mitoribosomes to translate mitochondrial mRNAs. The biogenesis of mitoribosomes is an intricate process involving multiple assembly factors. Among these factors, GTP-binding proteins (GTPBPs) play important roles. In bacterial systems, numerous GTPBPs are required for ribosome subunit maturation, with EngB being a GTPBP involved in the ribosomal large subunit assembly. In this study, we focus on exploring the function of GTPBP8, the human homolog of EngB. We find that ablation of GTPBP8 leads to the inhibition of mitochondrial translation, resulting in significant impairment of oxidative phosphorylation. Structural analysis of mitoribosomes from GTPBP8 knock-out cells shows the accumulation of mitoribosomal large subunit assembly intermediates that are incapable of forming functional monosomes. Furthermore, fPAR-CLIP analysis reveals that GTPBP8 is an RNA-binding protein that interacts specifically with the mitochondrial ribosome large subunit 16 S rRNA. Our study highlights the role of GTPBP8 as a component of the mitochondrial gene expression machinery involved in mitochondrial large subunit maturation.
    DOI:  https://doi.org/10.1038/s41467-024-50011-x
  4. Nat Struct Mol Biol. 2024 Jul 01.
    Asymmetric apical domain states of mitochondrial Hsp60 coordinate substrate engagement and chaperonin assembly.
    Julian R Braxton, Hao Shao, Eric Tse, Jason E Gestwicki, Daniel R Southworth.
      The mitochondrial chaperonin, mitochondrial heat shock protein 60 (mtHsp60), promotes the folding of newly imported and transiently misfolded proteins in the mitochondrial matrix, assisted by its co-chaperone mtHsp10. Despite its essential role in mitochondrial proteostasis, structural insights into how this chaperonin progresses through its ATP-dependent client folding cycle are not clear. Here, we determined cryo-EM structures of a hyperstable disease-associated human mtHsp60 mutant, V72I. Client density is identified in three distinct states, revealing interactions with the mtHsp60 apical domains and C termini that coordinate client positioning in the folding chamber. We further identify an asymmetric arrangement of the apical domains in the ATP state, in which an alternating up/down configuration positions interaction surfaces for simultaneous recruitment of mtHsp10 and client retention. Client is then fully encapsulated in mtHsp60-10, revealing prominent contacts at two discrete sites that potentially support maturation. These results identify distinct roles for the apical domains in coordinating client capture and progression through the chaperone cycle, supporting a conserved mechanism of group I chaperonin function.
    DOI:  https://doi.org/10.1038/s41594-024-01352-0
  5. Nat Genet. 2024 Jul 01.
    Mitochondrial genetics through the lens of single-cell multi-omics.
    Lena Nitsch, Caleb A Lareau, Leif S Ludwig.
      Mitochondria carry their own genetic information encoding for a subset of protein-coding genes and translational machinery essential for cellular respiration and metabolism. Despite its small size, the mitochondrial genome, its natural genetic variation and molecular phenotypes have been challenging to study using bulk sequencing approaches, due to its variation in cellular copy number, non-Mendelian modes of inheritance and propensity for mutations. Here we highlight emerging strategies designed to capture mitochondrial genetic variation across individual cells for lineage tracing and studying mitochondrial genetics in primary human cells and clinical specimens. We review recent advances surrounding single-cell mitochondrial genome sequencing and its integration with functional genomic readouts, including leveraging somatic mitochondrial DNA mutations as clonal markers that can resolve cellular population dynamics in complex human tissues. Finally, we discuss how single-cell whole mitochondrial genome sequencing approaches can be utilized to investigate mitochondrial genetics and its contribution to cellular heterogeneity and disease.
    DOI:  https://doi.org/10.1038/s41588-024-01794-8
  6. Nat Cell Biol. 2024 Jul 05.
    Functional multi-organelle units control inflammatory lipid metabolism of macrophages.
    Julia A Zimmermann, Kerstin Lucht, Manuel Stecher, Chahat Badhan, Katharina M Glaser, Maximilian W Epple, Lena R Koch, Ward Deboutte, Thomas Manke, Klaus Ebnet, Frauke Brinkmann, Olesja Fehler, Thomas Vogl, Ev-Marie Schuster, Anna Bremser, Joerg M Buescher, Angelika S Rambold.
      Eukaryotic cells contain several membrane-separated organelles to compartmentalize distinct metabolic reactions. However, it has remained unclear how these organelle systems are coordinated when cells adapt metabolic pathways to support their development, survival or effector functions. Here we present OrgaPlexing, a multi-spectral organelle imaging approach for the comprehensive mapping of six key metabolic organelles and their interactions. We use this analysis on macrophages, immune cells that undergo rapid metabolic switches upon sensing bacterial and inflammatory stimuli. Our results identify lipid droplets (LDs) as primary inflammatory responder organelle, which forms three- and four-way interactions with other organelles. While clusters with endoplasmic reticulum (ER) and mitochondria (mitochondria-ER-LD unit) help supply fatty acids for LD growth, the additional recruitment of peroxisomes (mitochondria-ER-peroxisome-LD unit) supports fatty acid efflux from LDs. Interference with individual components of these units has direct functional consequences for inflammatory lipid mediator synthesis. Together, we show that macrophages form functional multi-organellar units to support metabolic adaptation and provide an experimental strategy to identify organelle-metabolic signalling hubs.
    DOI:  https://doi.org/10.1038/s41556-024-01457-0
  7. Aging Cell. 2024 Jul 02. e14262
    Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity.
    Annika Traa, Allison Keil, Abdelrahman AlOkda, Suleima Jacob-Tomas, Aura A Tamez González, Shusen Zhu, Zenith Rudich, Jeremy M Van Raamsdonk.
      The dynamicity of the mitochondrial network is crucial for meeting the ever-changing metabolic and energy needs of the cell. Mitochondrial fission promotes the degradation and distribution of mitochondria, while mitochondrial fusion maintains mitochondrial function through the complementation of mitochondrial components. Previously, we have reported that mitochondrial networks are tubular, interconnected, and well-organized in young, healthy C. elegans, but become fragmented and disorganized with advancing age and in models of age-associated neurodegenerative disease. In this work, we examine the effects of increasing mitochondrial fission or mitochondrial fusion capacity by ubiquitously overexpressing the mitochondrial fission gene drp-1 or the mitochondrial fusion genes fzo-1 and eat-3, individually or in combination. We then measured mitochondrial function, mitochondrial network morphology, physiologic rates, stress resistance, and lifespan. Surprisingly, we found that overexpression of either mitochondrial fission or fusion machinery both resulted in an increase in mitochondrial fragmentation. Similarly, both mitochondrial fission and mitochondrial fusion overexpression strains have extended lifespans and increased stress resistance, which in the case of the mitochondrial fusion overexpression strains appears to be at least partially due to the upregulation of multiple pathways of cellular resilience in these strains. Overall, our work demonstrates that increasing the expression of mitochondrial fission or fusion genes extends lifespan and improves biological resilience without promoting the maintenance of a youthful mitochondrial network morphology. This work highlights the importance of the mitochondria for both resilience and longevity.
    Keywords:   C. elegans ; aging; biological resilience; genetics; lifespan; mitochondria; mitochondrial fission; mitochondrial fusion
    DOI:  https://doi.org/10.1111/acel.14262
  8. STAR Protoc. 2024 Jun 27. pii: S2666-1667(24)00326-5. [Epub ahead of print]5(3): 103161
    Protocol for detecting mitochondria extracellular vesicles of brown adipose tissue in mice.
    Flavia Tortolici, Claudia Di Biagio, Daniele Lettieri-Barbato, Katia Aquilano.
      Brown adipose tissue (BAT) is mitochondria rich, enabling high oxidative metabolism for non-shivering thermogenesis. The release of large/small extracellular vesicles (EVs) containing mitochondria or mitochondrial fragments, termed mito-EVs, may support mitochondrial quality control or intercellular communication. We present a protocol to isolate and characterize mito-EVs. We detail steps for BAT processing, cell debris removal, differential centrifugation (dC), and mito-EV analysis by flow cytometry and immunoblotting assays. For complete details on the use and execution of this protocol, please refer to Rosina et al.1.
    Keywords:  Cell Biology; Cell Membrane; Cell culture; Flow Cytometry; Metabolism; Molecular Biology; Protein Biochemistry
    DOI:  https://doi.org/10.1016/j.xpro.2024.103161
  9. Autophagy. 2024 Jul 04. 1-12
    Prohibitins, Phb1 and Phb2, function as Atg8 receptors to support yeast mitophagy and also play a negative regulatory role in Atg32 processing.
    Diana García-Chávez, Eunice Domínguez-Martín, Laura Kawasaki, Laura Ongay-Larios, Hilario Ruelas-Ramírez, Ariann E Mendoza-Martinez, Juan P Pardo, Soledad Funes, Roberto Coria.
      The prohibitins Phb1 and Phb2 assemble at the mitochondrial inner membrane to form a multi-dimeric complex. These scaffold proteins are highly conserved in eukaryotic cells, from yeast to mammals, and have been implicated in a variety of mitochondrial functions including aging, proliferation, and degenerative and metabolic diseases. In mammals, PHB2 regulates PINK1-PRKN mediated mitophagy by interacting with lipidated MAP1LC3B/LC3B. Despite their high conservation, prohibitins have not been linked to mitophagy in budding yeasts. In this study, we demonstrate that both Phb1 and Phb2 are required to sustain mitophagy in Saccharomyces cerevisiae. Prohibitin-dependent mitophagy requires formation of the Phb1-Phb2 complex and a conserved AIM/LIR-like motif identified in both yeast prohibitins. Furthermore, both Phb1 and Phb2 interact and exhibit mitochondrial colocalization with Atg8. Interestingly, we detected a basal C terminus processing of the mitophagy receptor Atg32 that depends on the presence of the i-AAA Yme1. In the absence of prohibitins this processing is highly enhanced but reverted by the inactivation of the rhomboid protease Pcp1. Together our results revealed a novel role of yeast prohibitins in mitophagy through its interaction with Atg8 and regulating an Atg32 proteolytic event. Abbreviation: AIM/LIR: Atg8-family interacting motif/LC3-interacting region; ANOVA: analysis of variance; ATG/Atg: autophagy related; C terminus/C-terminal: carboxyl terminus/carboxyl-terminal; GFP: green fluorescent protein; HA: human influenza hemagglutinin; Idh1: isocitrate dehydrogenase 1; MAP1C3B/LC3B: microtubule associated protein 1 light chain 3 beta; mCh: mCherry; MIM: mitochondrial inner membrane; MOM: mitochondrial outer membrane; N starvation: nitrogen starvation; N terminus: amino terminus; PARL: presenilin associated rhomboid like; Pcp1: processing of cytochrome c peroxidase 1; PCR: polymerase chain reaction; PGAM5: PGAM family member 5 mitochondrial serine/threonine protein phosphatase; PHBs/Phb: prohibitins; PINK1: PTEN induced kinase 1; PMSF: phenylmethylsulfonyl fluoride; PRKN: parkin RBR E3 ubiquitin protein ligase; SD: synthetic defined medium; SDS: sodium dodecyl sulfate; SMD-N: synthetic defined medium lacking nitrogen; WB: western blot; WT: wild type; Yme1: yeast mitochondrial escape 1; YPD: yeast extract-peptone-dextrose medium; YPLac: yeast extract-peptone-lactate medium.
    Keywords:  AIM/LIR motif; PARL; PINK1-PRKN; autophagy; i-AAA protease (Yme1); rhomboid protease (Pcp1)
    DOI:  https://doi.org/10.1080/15548627.2024.2371717
  10. Cell Metab. 2024 Jul 02. pii: S1550-4131(24)00236-5. [Epub ahead of print]36(7): 1436-1438
    Fit for purpose: Selecting the best mitochondrial DNA for the job.
    Sarah J Pickett, Robert W Taylor, Robert McFarland.
      The factors determining levels of pathogenic mitochondrial DNA in cells and tissues are critical to disease pathology but remain poorly understood and contentious. In Nature, Kotrys et al. published a single-cell-based analysis casting fresh light on this thorny problem and introduced a powerful new investigative tool.
    DOI:  https://doi.org/10.1016/j.cmet.2024.06.011
  11. Cell Death Dis. 2024 Jul 03. 15(7): 477
    A mitochondrial checkpoint to NF-κB signaling.
    Emma Guilbaud, Lorenzo Galluzzi.
      Mitochondrial dysfunction can elicit multiple inflammatory pathways, especially when apoptotic caspases are inhibited. Such an inflammatory program is negatively regulated by the autophagic disposal of permeabilized mitochondria. Recent data demonstrate that the ubiquitination of mitochondrial proteins is essential for NEMO-driven NF-kB activation downstream of mitochondrial permeabilization.
    DOI:  https://doi.org/10.1038/s41419-024-06868-3
  12. J Biol Chem. 2024 Jun 27. pii: S0021-9258(24)01999-9. [Epub ahead of print] 107498
    Bridging lipid metabolism and mitochondrial genome maintenance.
    Casadora Boone, Samantha C Lewis.
      Mitochondria are the nexus of cellular energy metabolism and major signaling hubs that integrate information from within and without the cell to implement cell function. Mitochondria harbor a distinct polyploid genome, mitochondrial DNA (mtDNA), that encodes respiratory chain components required for energy production. MtDNA mutation and depletion have been linked to obesity and metabolic syndrome in humans. At the cellular and subcellular levels, mtDNA synthesis is coordinated by membrane contact sites implicated in lipid transfer from the endoplasmic reticulum, tying genome maintenance to lipid storage and homeostasis. Here, we examine the relationship between mtDNA and lipid trafficking, the influence of lipotoxicity on mtDNA integrity, and how lipid metabolism may be disrupted in primary mtDNA disease.
    Keywords:  Mitochondria; lipid metabolism; lipotoxicity; mitochondrial DNA (mtDNA); mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2024.107498
  13. Life Sci Alliance. 2024 Sep;pii: e202302396. [Epub ahead of print]7(9):
    Trafficking of mitochondrial double-stranded RNA from mitochondria to the cytosol.
    Matthew R Krieger, Melania Abrahamian, Kevin L He, Sean Atamdede, Hesamedin Hakimjavadi, Milica Momcilovic, Dejerianne Ostrow, Simran Ds Maggo, Yik Pui Tsang, Xiaowu Gai, Guillaume F Chanfreau, David B Shackelford, Michael A Teitell, Carla M Koehler.
      In addition to mitochondrial DNA, mitochondrial double-stranded RNA (mtdsRNA) is exported from mitochondria. However, specific channels for RNA transport have not been demonstrated. Here, we begin to characterize channel candidates for mtdsRNA export from the mitochondrial matrix to the cytosol. Down-regulation of SUV3 resulted in the accumulation of mtdsRNAs in the matrix, whereas down-regulation of PNPase resulted in the export of mtdsRNAs to the cytosol. Targeting experiments show that PNPase functions in both the intermembrane space and matrix. Strand-specific sequencing of the double-stranded RNA confirms the mitochondrial origin. Inhibiting or down-regulating outer membrane proteins VDAC1/2 and BAK/BAX or inner membrane proteins PHB1/2 strongly attenuated the export of mtdsRNAs to the cytosol. The cytosolic mtdsRNAs subsequently localized to large granules containing the stress protein TIA-1 and activated the type 1 interferon stress response pathway. Abundant mtdsRNAs were detected in a subset of non-small-cell lung cancer cell lines that were glycolytic, indicating relevance in cancer biology. Thus, we propose that mtdsRNA is a new damage-associated molecular pattern that is exported from mitochondria in a regulated manner.
    DOI:  https://doi.org/10.26508/lsa.202302396
  14. Cell Metab. 2024 Jul 02. pii: S1550-4131(24)00227-4. [Epub ahead of print]36(7): 1433-1435
    From whence it came: Mitochondrial mRNA leaves, a protein returns.
    Kevin A Janssen, Angela Song.
      Small peptides have previously been reported to be encoded in mitochondrial rRNA and translated by cytosolic ribosomes. In this issue of Cell Metabolism, Hu et al. use mass spectrometry to identify a cytosolically translated protein, encoded instead in mitochondrial mRNA, that is surprisingly targeted back into the mitochondrial matrix.
    DOI:  https://doi.org/10.1016/j.cmet.2024.06.002
  15. PLoS Biol. 2024 Jul;22(7): e3002671
    Beyond fission and fusion-Diving into the mysteries of mitochondrial shape.
    Noga Preminger, Maya Schuldiner.
      Mitochondrial shape and network formation have been primarily associated with the well-established processes of fission and fusion. However, recent research has unveiled an intricate and multifaceted landscape of mitochondrial morphology that extends far beyond the conventional fission-fusion paradigm. These less-explored dimensions harbor numerous unresolved mysteries. This review navigates through diverse processes influencing mitochondrial shape and network formation, highlighting the intriguing complexities and gaps in our understanding of mitochondrial architecture. The exploration encompasses various scales, from biophysical principles governing membrane dynamics to molecular machineries shaping mitochondria, presenting a roadmap for future research in this evolving field.
    DOI:  https://doi.org/10.1371/journal.pbio.3002671
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