bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024–03–10
thirteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.
  2. Aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization.
  3. Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.
  4. Activity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo.
  5. NDUFS4 regulates cristae remodeling in diabetic kidney disease.
  6. CLU (clusterin) and PPARGC1A/PGC1α coordinately control mitophagy and mitochondrial biogenesis for oral cancer cell survival.
  7. Autophagy sustains mitochondrial respiration and determines resistance to BRAFV600E inhibition in thyroid carcinoma cells.
  8. Two ancient membrane pores mediate mitochondrial-nucleus membrane contact sites.
  9. PsAF5 functions as an essential adapter for PsPHB2-mediated mitophagy under ROS stress in Phytophthora sojae.
  10. ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission.
  11. Mitochondrial DNA marks multiple sclerosis.
  12. The interplay between mitochondrial dynamics and autophagy: From a key homeostatic mechanism to a driver of pathology.
  13. An unexpected journey for BNIP3.
  1. Cell Stem Cell. 2024 Mar 07. pii: S1934-5909(24)00047-X. [Epub ahead of print]31(3): 359-377.e10
    A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.
    Massimo Bonora, Claudia Morganti, Nick van Gastel, Kyoko Ito, Enrica Calura, Ilaria Zanolla, Letizia Ferroni, Yang Zhang, Yookyung Jung, Gabriele Sales, Paolo Martini, Takahisa Nakamura, Francesco Massimo Lasorsa, Toren Finkel, Charles P Lin, Barbara Zavan, Paolo Pinton, Irene Georgakoudi, Chiara Romualdi, David T Scadden, Keisuke Ito.
      Mitochondrial fatty acid oxidation (FAO) is essential for hematopoietic stem cell (HSC) self-renewal; however, the mechanism by which mitochondrial metabolism controls HSC fate remains unknown. Here, we show that within the hematopoietic lineage, HSCs have the largest mitochondrial NADPH pools, which are required for proper HSC cell fate and homeostasis. Bioinformatic analysis of the HSC transcriptome, biochemical assays, and genetic inactivation of FAO all indicate that FAO-generated NADPH fuels cholesterol synthesis in HSCs. Interference with FAO disturbs the segregation of mitochondrial NADPH toward corresponding daughter cells upon single HSC division. Importantly, we have found that the FAO-NADPH-cholesterol axis drives extracellular vesicle (EV) biogenesis and release in HSCs, while inhibition of EV signaling impairs HSC self-renewal. These data reveal the existence of a mitochondrial NADPH-cholesterol axis for EV biogenesis that is required for hematopoietic homeostasis and highlight the non-stochastic nature of HSC fate determination.
    Keywords:  HSC self-renewal; NADPH; cholesterol; exosomes; extracellular vesicles; fate determination; fatty acid oxidation; hematopoietic stem cell; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.stem.2024.02.004
  2. Cell Metab. 2024 Mar 01. pii: S1550-4131(24)00057-3. [Epub ahead of print]
    Aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization.
    Dingfeng Li, Xinyi Gao, Xiaolin Ma, Ming Wang, Chuandong Cheng, Tian Xue, Feng Gao, Yong Shen, Juan Zhang, Qiang Liu.
      Mitochondrial cristae, infoldings of the mitochondrial inner membrane, undergo aberrant changes in their architecture with age. However, the underlying molecular mechanisms and their contribution to brain aging are largely elusive. Here, we observe an age-dependent accumulation of Glu-5'tsRNA-CTC, a transfer-RNA-derived small RNA (tsRNA), derived from nuclear-encoded tRNAGlu in the mitochondria of glutaminergic neurons. Mitochondrial Glu-5'tsRNA-CTC disrupts the binding of mt-tRNALeu and leucyl-tRNA synthetase2 (LaRs2), impairing mt-tRNALeu aminoacylation and mitochondria-encoded protein translation. Mitochondrial translation defects disrupt cristae organization, leading to damaged glutaminase (GLS)-dependent glutamate formation and reduced synaptosomal glutamate levels. Moreover, reduction of Glu-5'tsRNA-CTC protects aged brains from age-related defects in mitochondrial cristae organization, glutamate metabolism, synaptic structures, and memory. Thus, beyond illustrating a physiological role for normal mitochondrial cristae ultrastructure in maintaining glutamate levels, our study defines a pathological role for tsRNAs in brain aging and age-related memory decline.
    Keywords:  angiogenin; brain aging; cristae organization; glutamate metabolism; memory decline; mitochondria; mitochondrial translation; tRNA-derived small RNAs
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.011
  3. Nat Commun. 2024 Mar 02. 15(1): 1931
    Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.
    Martha M Zarou, Kevin M Rattigan, Daniele Sarnello, Engy Shokry, Amy Dawson, Angela Ianniciello, Karen Dunn, Mhairi Copland, David Sumpton, Alexei Vazquez, G Vignir Helgason.
      Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in anti-cancer therapy. Here, we reveal that mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells (LSCs). We demonstrate that inhibition of mitochondrial 1C metabolism through impairment of de novo purine synthesis has a cytostatic effect on chronic myeloid leukaemia (CML) cells. Consequently, changes in purine nucleotide levels lead to activation of AMPK signalling and suppression of mTORC1 activity. Notably, suppression of mitochondrial 1C metabolism increases expression of erythroid differentiation markers. Moreover, we find that increased differentiation occurs independently of AMPK signalling and can be reversed through reconstitution of purine levels and reactivation of mTORC1. Of clinical relevance, we identify that combination of 1C metabolism inhibition with imatinib, a frontline treatment for CML patients, decreases the number of therapy-resistant CML LSCs in a patient-derived xenograft model. Our results highlight a role for folate metabolism and purine sensing in stem cell fate decisions and leukaemogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-46114-0
  4. Nat Commun. 2024 Mar 08. 15(1): 2142
    Activity-dependent compartmentalization of dendritic mitochondria morphology through local regulation of fusion-fission balance in neurons in vivo.
    Daniel M Virga, Stevie Hamilton, Bertha Osei, Abigail Morgan, Parker Kneis, Emiliano Zamponi, Natalie J Park, Victoria L Hewitt, David Zhang, Kevin C Gonzalez, Fiona M Russell, D Grahame Hardie, Julien Prudent, Erik Bloss, Attila Losonczy, Franck Polleux, Tommy L Lewis.
      Neuronal mitochondria play important roles beyond ATP generation, including Ca2+ uptake, and therefore have instructive roles in synaptic function and neuronal response properties. Mitochondrial morphology differs significantly between the axon and dendrites of a given neuronal subtype, but in CA1 pyramidal neurons (PNs) of the hippocampus, mitochondria within the dendritic arbor also display a remarkable degree of subcellular, layer-specific compartmentalization. In the dendrites of these neurons, mitochondria morphology ranges from highly fused and elongated in the apical tuft, to more fragmented in the apical oblique and basal dendritic compartments, and thus occupy a smaller fraction of dendritic volume than in the apical tuft. However, the molecular mechanisms underlying this striking degree of subcellular compartmentalization of mitochondria morphology are unknown, precluding the assessment of its impact on neuronal function. Here, we demonstrate that this compartment-specific morphology of dendritic mitochondria requires activity-dependent, Ca2+ and Camkk2-dependent activation of AMPK and its ability to phosphorylate two direct effectors: the pro-fission Drp1 receptor Mff and the recently identified anti-fusion, Opa1-inhibiting protein, Mtfr1l. Our study uncovers a signaling pathway underlying the subcellular compartmentalization of mitochondrial morphology in dendrites of neurons in vivo through spatially precise and activity-dependent regulation of mitochondria fission/fusion balance.
    DOI:  https://doi.org/10.1038/s41467-024-46463-w
  5. Nat Commun. 2024 Mar 04. 15(1): 1965
    NDUFS4 regulates cristae remodeling in diabetic kidney disease.
    Koki Mise, Jianyin Long, Daniel L Galvan, Zengchun Ye, Guizhen Fan, Rajesh Sharma, Irina I Serysheva, Travis I Moore, Collene R Jeter, M Anna Zal, Motoo Araki, Jun Wada, Paul T Schumacker, Benny H Chang, Farhad R Danesh.
      The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generate diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that conditional male mice with genetic overexpression of Ndufs4 exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping protein STOML2 in linking NDUFS4 with improved cristae morphology. Together, we provide the evidence on the central role of NDUFS4 as a regulator of cristae remodeling and mitochondrial function in kidney podocytes. We propose that targeting NDUFS4 represents a promising approach to slow the progression of DKD.
    DOI:  https://doi.org/10.1038/s41467-024-46366-w
  6. Autophagy. 2024 Mar 06. 1-25
    CLU (clusterin) and PPARGC1A/PGC1α coordinately control mitophagy and mitochondrial biogenesis for oral cancer cell survival.
    Prakash P Praharaj, Srimanta Patra, Amruta Singh, Debasna P Panigrahi, Hwa Y Lee, Mohammad F Kabir, Muhammad K Hossain, Samir K Patra, Birija S Patro, Shankargouda Patil, Daniel J Klionsky, Han J Chae, Sujit K Bhutia.
      Mitophagy involves the selective elimination of defective mitochondria during chemotherapeutic stress to maintain mitochondrial homeostasis and sustain cancer growth. Here, we showed that CLU (clusterin) is localized to mitochondria to induce mitophagy controlling mitochondrial damage in oral cancer cells. Moreover, overexpression and knockdown of CLU establish its mitophagy-specific role, where CLU acts as an adaptor protein that coordinately interacts with BAX and LC3 recruiting autophagic machinery around damaged mitochondria in response to cisplatin treatment. Interestingly, CLU triggers class III phosphatidylinositol 3-kinase (PtdIns3K) activity around damaged mitochondria, and inhibition of mitophagic flux causes the accumulation of excessive mitophagosomes resulting in reactive oxygen species (ROS)-dependent apoptosis during cisplatin treatment in oral cancer cells. In parallel, we determined that PPARGC1A/PGC1α (PPARG coactivator 1 alpha) activates mitochondrial biogenesis during CLU-induced mitophagy to maintain the mitochondrial pool. Intriguingly, PPARGC1A inhibition through small interfering RNA (siPPARGC1A) and pharmacological inhibitor (SR-18292) treatment counteracts CLU-dependent cytoprotection leading to mitophagy-associated cell death. Furthermore, co-treatment of SR-18292 with cisplatin synergistically suppresses tumor growth in oral cancer xenograft models. In conclusion, CLU and PPARGC1A are essential for sustained cancer cell growth by activating mitophagy and mitochondrial biogenesis, respectively, and their inhibition could provide better therapeutic benefits against oral cancer.
    Keywords:  Clusterin; PPARGC1A/PGC1α; mitochondrial biogenesis; mitophagy; mitophagy-associated cell death
    DOI:  https://doi.org/10.1080/15548627.2024.2309904
  7. Autophagy. 2024 Mar 04. 1-15
    Autophagy sustains mitochondrial respiration and determines resistance to BRAFV600E inhibition in thyroid carcinoma cells.
    Sergio Díaz-Gago, Javier Vicente-Gutiérrez, Jose Manuel Ruiz-Rodríguez, Josep Calafell, Alicia Álvarez-Álvarez, Marina Lasa, Antonio Chiloeches, Pablo Baquero.
      BRAFV600E is the most prevalent mutation in thyroid cancer and correlates with poor prognosis and therapy resistance. Although selective inhibitors of BRAFV600E have been developed, more advanced tumors such as anaplastic thyroid carcinomas show a poor response in clinical trials. Therefore, the study of alternative survival mechanisms is needed. Since metabolic changes have been related to malignant progression, in this work we explore metabolic dependencies of thyroid tumor cells to exploit them therapeutically. Our results show that respiration of thyroid carcinoma cells is highly dependent on fatty acid oxidation and, in turn, fatty acid mitochondrial availability is regulated through macroautophagy/autophagy. Furthermore, we show that both lysosomal inhibition and the knockout of the essential autophagy gene, ATG7, lead to enhanced lipolysis; although this effect is not essential for survival of thyroid carcinoma cells. We also demonstrate that following inhibition of either autophagy or fatty acid oxidation, thyroid tumor cells compensate oxidative phosphorylation deficiency with an increase in glycolysis. In contrast to lipolysis induction, upon autophagy inhibition, glycolytic boost in autophagy-deficient cells is essential for survival and, importantly, correlates with a higher sensitivity to the BRAFV600E selective inhibitor, vemurafenib. In agreement, downregulation of the glycolytic pathway results in enhanced mitochondrial respiration and vemurafenib resistance. Our work provides new insights into the role of autophagy in thyroid cancer metabolism and supports mitochondrial targeting in combination with vemurafenib to eliminate BRAFV600E-positive thyroid carcinoma cells.Abbreviations: AMP: adenosine monophosphate; ATC: anaplastic thyroid carcinoma; ATG: autophagy related; ATP: adenosine triphosphate; BRAF: B-Raf proto-oncogene, serine/threonine kinase; Cas9: CRISPR-associated protein; CREB: cAMP responsive element binding protein; CRISPR: clustered regularly interspaced short palindromic repeats; 2DG: 2-deoxyglucose; FA: fatty acid; FAO: fatty acid oxidation; FASN: fatty acid synthase; FCCP: trifluoromethoxy carbonyl cyanide phenylhydrazone; LAMP1: lysosomal associated membrane protein 1; LIPE/HSL: lipase E, hormone sensitive type; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; PRKA/PKA: protein kinase cAMP-activated; PTC: papillary thyroid carcinoma; SREBF1/SREBP1: sterol regulatory element binding transcription factor 1.
    Keywords:  Cancer metabolism; fatty acid oxidation; glycolysis; oxidative phosphorylation; thyroid cancer; vemurafenib resistance
    DOI:  https://doi.org/10.1080/15548627.2024.2312790
  8. J Cell Biol. 2024 Apr 01. pii: e202304075. [Epub ahead of print]223(4):
    Two ancient membrane pores mediate mitochondrial-nucleus membrane contact sites.
    Jana Ovciarikova, Shikha Shikha, Alice Lacombe, Flavie Courjol, Rosalind McCrone, Wasim Hussain, Andrew Maclean, Leandro Lemgruber, Erica S Martins-Duarte, Mathieu Gissot, Lilach Sheiner.
      Coordination between nucleus and mitochondria is essential for cell survival, and thus numerous communication routes have been established between these two organelles over eukaryotic cell evolution. One route for organelle communication is via membrane contact sites, functional appositions formed by molecular tethers. We describe a novel nuclear-mitochondrial membrane contact site in the protozoan Toxoplasma gondii. We have identified specific contacts occurring at the nuclear pore and demonstrated an interaction between components of the nuclear pore and the mitochondrial protein translocon, highlighting them as molecular tethers. Genetic disruption of the nuclear pore or the TOM translocon components, TgNup503 or TgTom40, respectively, result in contact site reduction, supporting their potential involvement in this tether. TgNup503 depletion further leads to specific mitochondrial morphology and functional defects, supporting a role for nuclear-mitochondrial contacts in mediating their communication. The discovery of a contact formed through interaction between two ancient mitochondrial and nuclear complexes sets the ground for better understanding of mitochondrial-nuclear crosstalk in eukaryotes.
    DOI:  https://doi.org/10.1083/jcb.202304075
  9. Nat Commun. 2024 Mar 04. 15(1): 1967
    PsAF5 functions as an essential adapter for PsPHB2-mediated mitophagy under ROS stress in Phytophthora sojae.
    Wenhao Li, Hongwei Zhu, Jinzhu Chen, Binglu Ru, Qin Peng, Jianqiang Miao, Xili Liu.
      Host-derived reactive oxygen species (ROS) are an important defense means to protect against pathogens. Although mitochondria are the main intracellular targets of ROS, how pathogens regulate mitochondrial physiology in response to oxidative stress remains elusive. Prohibitin 2 (PHB2) is an inner mitochondrial membrane (IMM) protein, recognized as a mitophagy receptor in animals and fungi. Here, we find that an ANK and FYVE domain-containing protein PsAF5, is an adapter of PsPHB2, interacting with PsATG8 under ROS stress. Unlike animal PHB2 that can recruit ATG8 directly to mitochondria, PsPHB2 in Phytophthora sojae cannot recruit PsATG8 to stressed mitochondria without PsAF5. PsAF5 deletion impairs mitophagy under ROS stress and increases the pathogen's sensitivity to H2O2, resulting in the attenuation of P. sojae virulence. This discovery of a PsPHB2-PsATG8 adapter (PsAF5) in plant-pathogenic oomycetes reveals that mitophagy induction by IMM proteins is conserved in eukaryotes, but with differences in the details of ATG8 recruitment.
    DOI:  https://doi.org/10.1038/s41467-024-46290-z
  10. Cell Death Dis. 2024 Mar 02. 15(3): 184
    ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission.
    Palamou Das, Oishee Chakrabarti.
      Dynamin related protein 1 (DRP1), a pivotal mitochondrial fission protein, is post-translationally modified by multiple mechanisms. Here we identify a new post-translational modification of DRP1 by the ubiquitin-like protein, interferon-stimulated gene 15 (ISG15). DRP1 ISGylation is mediated by ISG15 E3 ligase, HERC5; this promotes mitochondrial fission. DeISGylation of DRP1 however leads to hyperfusion. Heterologous expression of SARS-CoV2 PLpro, a deISGylating enzyme, results in similar mitochondrial filamentation, significant decrease in total DRP1 protein levels and efflux of mtDNA. We report that deISGylated DRP1 gets ubiquitylated and degraded by TRIM25, instead of PARKIN and MITOL. While the cytosolic pool of DRP1 is primarily ISGylated, both mitochondrial and cytosolic fractions may be ubiquitylated. It is known that phosphorylation of DRP1 at S616 residue regulates its mitochondrial localisation; we show that ISGylation of phospho-DRP1 (S616) renders fission competence at mitochondria. This is significant because DRP1 ISGylation affects its functionality and mitochondrial dynamics in Alzheimer's disease pathophysiology.
    DOI:  https://doi.org/10.1038/s41419-024-06543-7
  11. Nat Rev Neurol. 2024 Mar 05.
    Mitochondrial DNA marks multiple sclerosis.
    Ian Fyfe.
      
    DOI:  https://doi.org/10.1038/s41582-024-00948-w
  12. Semin Cell Dev Biol. 2024 Mar 01. pii: S1084-9521(24)00022-3. [Epub ahead of print]161-162 1-19
    The interplay between mitochondrial dynamics and autophagy: From a key homeostatic mechanism to a driver of pathology.
    Alice Lacombe, Luca Scorrano.
      The complex relationship between mitochondrial dynamics and autophagy illustrates how two cellular housekeeping processes are intimately linked, illuminating fundamental principles of cellular homeostasis and shedding light on disparate pathological conditions including several neurodegenerative disorders. Here we review the basic tenets of mitochondrial dynamics i.e., the concerted balance between fusion and fission of the organelle, and its interplay with macroautophagy and selective mitochondrial autophagy, also dubbed mitophagy, in the maintenance of mitochondrial quality control and ultimately in cell viability. We illustrate how conditions of altered mitochondrial dynamics reverberate on autophagy and vice versa. Finally, we illustrate how altered interplay between these two key cellular processes participates in the pathogenesis of human disorders affecting multiple organs and systems.
    Keywords:  Mitochondria; autophagy; diseases; fusion-fission; mitophagy
    DOI:  https://doi.org/10.1016/j.semcdb.2024.02.001
  13. Autophagy. 2024 Mar 06. 1-2
    An unexpected journey for BNIP3.
    José M Delgado, Christopher J Shoemaker.
      Mitophagy is a cellular process that enables the selective degradation of damaged, dysfunctional, or superfluous mitochondria. During mitophagy, specific proteins recognize and tag mitochondria for degradation. These tagged mitochondria are engulfed by specialized structures called phagophores that then mature into autophagosomes/mitophagosomes. Mitophagosomes subsequently transport their mitochondrial cargo to lysosomes, where the mitochondria are broken down and recycled. While the PINK1-PRKN-dependent mitophagy pathway is well understood, mitophagy can also occur independently of this pathway. BNIP3 and BNIP3L/NIX, paralogous membrane proteins on the outer mitochondrial membrane (OMM), serve as ubiquitin-independent mitophagy receptors. Historically, BNIP3 regulation was thought to be primarily transcriptional through HIF1A (hypoxia inducible factor 1 subunit alpha). However, recent work has revealed a significant post-translational dimension, highlighting the strong role of the ubiquitin-proteasome system (UPS) in BNIP3 regulation. With these emerging concepts in mind, we aimed to develop a unified understanding of how steady-state levels of BNIP3 are established and maintained and how this regulation governs underlying cell physiology.
    Keywords:  BNIP3; EMC; ER membrane protein complex; NIX; membrane trafficking; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2312038
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:23.