bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022‒12‒18
twelve papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Endosomal lipid signaling reshapes the endoplasmic reticulum to control mitochondrial function.
  2. NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy.
  3. Opa1 and Drp1 reciprocally regulate cristae morphology, ETC function, and NAD+ regeneration in KRas-mutant lung adenocarcinoma.
  4. The mitochondrial UPR regulator ATF5 promotes intestinal barrier function via control of the satiety response.
  5. Mechanisms of ion selectivity and throughput in the mitochondrial calcium uniporter.
  6. Diversity of mitophagy pathways at a glance.
  7. Thermoporter: a new regulatory mechanism for mitochondrial calcium uniporter activity.
  8. Methods to Assess the Role of PARPs in Regulating Mitochondrial Oxidative Function.
  9. Q-Flux: A method to assess hepatic mitochondrial succinate dehydrogenase, methylmalonyl-CoA mutase, and glutaminase fluxes in vivo.
  10. Mitochondrial dynamics proteins as emerging drug targets.
  11. An AAA-ATPase links mitochondrial division with DNA nucleoids.
  12. Cilia bent out of shape over dysfunctional astrocyte mitochondria.
  1. Science. 2022 Dec 16. 378(6625): eabq5209
    Endosomal lipid signaling reshapes the endoplasmic reticulum to control mitochondrial function.
    Wonyul Jang, Dmytro Puchkov, Paula Samsó, YongTian Liang, Michal Nadler-Holly, Stephan J Sigrist, Ulrich Kintscher, Fan Liu, Kamel Mamchaoui, Vincent Mouly, Volker Haucke.
      Cells respond to fluctuating nutrient supply by adaptive changes in organelle dynamics and in metabolism. How such changes are orchestrated on a cell-wide scale is unknown. We show that endosomal signaling lipid turnover by MTM1, a phosphatidylinositol 3-phosphate [PI(3)P] 3-phosphatase mutated in X-linked centronuclear myopathy in humans, controls mitochondrial morphology and function by reshaping the endoplasmic reticulum (ER). Starvation-induced endosomal recruitment of MTM1 impairs PI(3)P-dependent contact formation between tubular ER membranes and early endosomes, resulting in the conversion of ER tubules into sheets, the inhibition of mitochondrial fission, and sustained oxidative metabolism. Our results unravel an important role for early endosomal lipid signaling in controlling ER shape and, thereby, mitochondrial form and function to enable cells to adapt to fluctuating nutrient environments.
    DOI:  https://doi.org/10.1126/science.abq5209
  2. EMBO J. 2022 Dec 14. e111372
    NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy.
    Tetsushi Kataura, Elsje G Otten, Yoana Rabanal-Ruiz, Elias Adriaenssens, Francesca Urselli, Filippo Scialo, Lanyu Fan, Graham R Smith, William M Dawson, Xingxiang Chen, Wyatt W Yue, Agnieszka K Bronowska, Bernadette Carroll, Sascha Martens, Michael Lazarou, Viktor I Korolchuk.
      Mitophagy, the elimination of mitochondria via the autophagy-lysosome pathway, is essential for the maintenance of cellular homeostasis. The best characterised mitophagy pathway is mediated by stabilisation of the protein kinase PINK1 and recruitment of the ubiquitin ligase Parkin to damaged mitochondria. Ubiquitinated mitochondrial surface proteins are recognised by autophagy receptors including NDP52 which initiate the formation of an autophagic vesicle around the mitochondria. Damaged mitochondria also generate reactive oxygen species (ROS) which have been proposed to act as a signal for mitophagy, however the mechanism of ROS sensing is unknown. Here we found that oxidation of NDP52 is essential for the efficient PINK1/Parkin-dependent mitophagy. We identified redox-sensitive cysteine residues involved in disulphide bond formation and oligomerisation of NDP52 on damaged mitochondria. Oligomerisation of NDP52 facilitates the recruitment of autophagy machinery for rapid mitochondrial degradation. We propose that redox sensing by NDP52 allows mitophagy to function as a mechanism of oxidative stress response.
    Keywords:  NDP52; autophagy; mitophagy; p62; redox
    DOI:  https://doi.org/10.15252/embj.2022111372
  3. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01710-7. [Epub ahead of print]41(11): 111818
    Opa1 and Drp1 reciprocally regulate cristae morphology, ETC function, and NAD+ regeneration in KRas-mutant lung adenocarcinoma.
    Dane T Sessions, Kee-Beom Kim, Jennifer A Kashatus, Nikolas Churchill, Kwon-Sik Park, Marty W Mayo, Hiromi Sesaki, David F Kashatus.
      Oncogenic KRas activates mitochondrial fission through Erk-mediated phosphorylation of the mitochondrial fission GTPase Drp1. Drp1 deletion inhibits tumorigenesis of KRas-driven pancreatic cancer, but the role of mitochondrial dynamics in other Ras-driven malignancies is poorly defined. Here we show that in vitro and in vivo growth of KRas-driven lung adenocarcinoma is unaffected by deletion of Drp1 but is inhibited by deletion of Opa1, the GTPase that regulates inner membrane fusion and proper cristae morphology. Mechanistically, Opa1 knockout disrupts cristae morphology and inhibits electron transport chain (ETC) assembly and activity, which inhibits tumor cell proliferation through loss of NAD+ regeneration. Simultaneous inactivation of Drp1 and Opa1 restores cristae morphology, ETC activity, and cell proliferation indicating that mitochondrial fission activity drives ETC dysfunction induced by Opa1 knockout. Our results support a model in which mitochondrial fission events disrupt cristae structure, and tumor cells with hyperactive fission activity require Opa1 activity to maintain ETC function.
    Keywords:  CP: Cancer; Drp1; ETC; KRas; NAD; Opa1; cancer; cristae; fission; fusion; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2022.111818
  4. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01677-1. [Epub ahead of print]41(11): 111789
    The mitochondrial UPR regulator ATF5 promotes intestinal barrier function via control of the satiety response.
    Douja Chamseddine, Siraje A Mahmud, Aundrea K Westfall, Todd A Castoe, Rance E Berg, Mark W Pellegrino.
      Organisms use several strategies to mitigate mitochondrial stress, including the activation of the mitochondrial unfolded protein response (UPRmt). The UPRmt in Caenorhabditis elegans, regulated by the transcription factor ATFS-1, expands on this recovery program by inducing an antimicrobial response against pathogens that target mitochondrial function. Here, we show that the mammalian ortholog of ATFS-1, ATF5, protects the host during infection with enteric pathogens but, unexpectedly, by maintaining the integrity of the intestinal barrier. Intriguingly, ATF5 supports intestinal barrier function by promoting a satiety response that prevents obesity and associated hyperglycemia. This consequently averts dysregulated glucose metabolism that is detrimental to barrier function. Mechanistically, we show that intestinal ATF5 stimulates the satiety response by transcriptionally regulating the gastrointestinal peptide hormone cholecystokinin, which promotes the secretion of the hormone leptin. We propose that ATF5 protects the host from enteric pathogens by promoting intestinal barrier function through a satiety-response-mediated metabolic control mechanism.
    Keywords:  ATF5; CP: Metabolism; CP: Molecular biology; UPR(mt); cholecystokinin; colitis; epithelial barrier; host-pathogen interaction; hyperglycemia; leptin; mitochondria; satiety
    DOI:  https://doi.org/10.1016/j.celrep.2022.111789
  5. Sci Adv. 2022 Dec 16. 8(50): eade1516
    Mechanisms of ion selectivity and throughput in the mitochondrial calcium uniporter.
    Bryce D Delgado, Stephen B Long.
      The mitochondrial calcium uniporter, which regulates aerobic metabolism by catalyzing mitochondrial Ca2+ influx, is arguably the most selective ion channel known. The mechanisms for this exquisite Ca2+ selectivity have not been defined. Here, using a reconstituted system, we study the electrical properties of the channel's minimal Ca2+-conducting complex, MCU-EMRE, from Tribolium castaneum to probe ion selectivity mechanisms. The wild-type TcMCU-EMRE complex recapitulates hallmark electrophysiological properties of endogenous Uniporter channels. Through interrogation of pore-lining mutants, we find that a ring of glutamate residues, the "E-locus," serves as the channel's selectivity filter. Unexpectedly, a nearby "D-locus" at the mouth of the pore has diminutive influence on selectivity. Anomalous mole fraction effects indicate that multiple Ca2+ ions are accommodated within the E-locus. By facilitating ion-ion interactions, the E-locus engenders both exquisite Ca2+ selectivity and high ion throughput. Direct comparison with structural information yields the basis for selective Ca2+ conduction by the channel.
    DOI:  https://doi.org/10.1126/sciadv.ade1516
  6. J Cell Sci. 2022 Dec 01. pii: jcs259748. [Epub ahead of print]135(23):
    Diversity of mitophagy pathways at a glance.
    Ian G Ganley, Anne Simonsen.
      Mitochondria are crucial organelles that play a central role in various cell signaling and metabolic pathways. A healthy mitochondrial population is maintained through a series of quality control pathways and requires a fine-tuned balance between mitochondrial biogenesis and degradation. Defective targeting of dysfunctional mitochondria to lysosomes through mitophagy has been linked to several diseases, but the underlying mechanisms and the relative importance of distinct mitophagy pathways in vivo are largely unknown. In this Cell Science at a Glance and the accompanying poster, we describe our current understanding of how parts of, or whole, mitochondria are recognized by the autophagic machinery and targeted to lysosomes for degradation. We also discuss how this might be regulated under different physiological conditions to maintain mitochondrial and cellular health.
    Keywords:  BNIP3; HIF1; Mitochondria; Mitophagy; NIX; PINK1; Parkin; SLR; Selective autophagy
    DOI:  https://doi.org/10.1242/jcs.259748
  7. Trends Cell Biol. 2022 Dec 12. pii: S0962-8924(22)00259-8. [Epub ahead of print]
    Thermoporter: a new regulatory mechanism for mitochondrial calcium uniporter activity.
    Kaili Xue, Dongmei Wu, Yifu Qiu.
      The mitochondrial calcium uniporter (MCU) controls mitochondrial bioenergetics, and its activity varies greatly between tissues. Here, we highlight a recently identified MCU-EMRE-UCP1 complex, named thermoporter, in the adaptive thermogenesis of brown adipose tissue (BAT). The thermoporter enhances MCU activity to promote thermogenic metabolism, demonstrating a BAT-specific regulation for MCU activity.
    DOI:  https://doi.org/10.1016/j.tcb.2022.11.008
  8. Methods Mol Biol. 2023 ;2609 227-249
    Methods to Assess the Role of PARPs in Regulating Mitochondrial Oxidative Function.
    Tünde Kovács, Boglárka Rauch, Edit Mikó, Péter Bai.
      PARP enzymes are involved in metabolic regulation and impact on a plethora of cellular metabolic pathways, among them, mitochondrial oxidative metabolism. The detrimental effects of PARP1 overactivation upon oxidative stress on mitochondrial oxidative metabolism was discovered in 1998. Since then, there was an enormous blooming in the understanding of the interplay between PARPs and mitochondria. Mitochondrial activity can be assessed by a comprehensive set of methods that we aim to introduce here.
    Keywords:  ARTD; Differentiation; Flow cytometry; Mitochondria; Mitochondrial fission; Mitochondrial fusion; Mitochondrial morphology; Oximetry; PARP; Seahorse extracellular flux analyzer; Substrate preference; Δψ
    DOI:  https://doi.org/10.1007/978-1-0716-2891-1_14
  9. Cell Metab. 2022 Dec 08. pii: S1550-4131(22)00502-2. [Epub ahead of print]
    Q-Flux: A method to assess hepatic mitochondrial succinate dehydrogenase, methylmalonyl-CoA mutase, and glutaminase fluxes in vivo.
    Brandon T Hubbard, Traci E LaMoia, Leigh Goedeke, Rafael C Gaspar, Katrine D Galsgaard, Mario Kahn, Graeme F Mason, Gerald I Shulman.
      The mammalian succinate dehydrogenase (SDH) complex has recently been shown as capable of operating bidirectionally. Here, we develop a method (Q-Flux) capable of measuring absolute rates of both forward (VSDH(F)) and reverse (VSDH(R)) flux through SDH in vivo while also deconvoluting the amount of glucose derived from four discreet carbon sources in the liver. In validation studies, a mitochondrial uncoupler increased net SDH flux by >100% in awake rodents but also increased SDH cycling. During hyperglucagonemia, attenuated pyruvate cycling enhances phosphoenolpyruvate carboxykinase efficiency to drive increased gluconeogenesis, which is complemented by increased glutaminase (GLS) flux, methylmalonyl-CoA mutase (MUT) flux, and glycerol conversion to glucose. During hyperinsulinemic-euglycemic clamp, both pyruvate carboxylase and GLS are suppressed, while VSDH(R) is increased. Unstimulated MUT is a minor anaplerotic reaction but is readily induced by small amounts of propionate, which elicits glucagon-like metabolic rewiring. Taken together, Q-Flux yields a comprehensive picture of hepatic mitochondrial metabolism and should be broadly useful to researchers.
    Keywords:  anaplerosis; glucagon; glutaminase; insulin; mass spectrometry; metabolic flux analysis; methylmalonyl-CoA mutase; mitochondrial metabolism; propionate; succinate dehydrogenase
    DOI:  https://doi.org/10.1016/j.cmet.2022.11.011
  10. Trends Pharmacol Sci. 2022 Dec 07. pii: S0165-6147(22)00254-1. [Epub ahead of print]
    Mitochondrial dynamics proteins as emerging drug targets.
    Emmanouil Zacharioudakis, Evripidis Gavathiotis.
      The importance of mitochondrial dynamics, the physiological process of mitochondrial fusion and fission, in regulating diverse cellular functions and cellular fitness has been well established. Several pathologies are associated with aberrant mitochondrial fusion or fission that is often a consequence of deregulated mitochondrial dynamics proteins; however, pharmacological targeting of these proteins has been lacking and is challenged by complex molecular mechanisms. Recent studies have advanced our understanding in this area and have enabled rational drug design and chemical screening strategies. We provide an updated overview of the regulatory mechanisms of fusion and fission proteins, their structure-function relationships, and the discovery of pharmacological modulators demonstrating their therapeutic potential. These advances provide exciting opportunities for the development of prototype therapeutics for various diseases.
    Keywords:  activators; fission; fusion; inhibitors; mitochondria; mitochondrial dynamics; mitochondrial structure
    DOI:  https://doi.org/10.1016/j.tips.2022.11.004
  11. Proc Natl Acad Sci U S A. 2022 Dec 20. 119(51): e2217949119
    An AAA-ATPase links mitochondrial division with DNA nucleoids.
    Nelson Yeung, Miho Iijima, Hiromi Sesaki.
      
    DOI:  https://doi.org/10.1073/pnas.2217949119
  12. J Cell Biol. 2023 Jan 02. pii: e202211123. [Epub ahead of print]222(1):
    Cilia bent out of shape over dysfunctional astrocyte mitochondria.
    Rachel M Bear, Tamara Caspary.
      Mitochondrial dysfunction in astrocytes drives neurodegenerative brain pathology. In this issue, Ignatenko et al. (2022. J. Cell. Biol.https://doi.org/10.1083/jcb.202203019) discover a novel connection between cilia and mitochondria in astrocytes, whereby mitochondrial dysfunction leads to abnormal cilia structure and a motile cilia program.
    DOI:  https://doi.org/10.1083/jcb.202211123
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