bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024‒06‒23
fifteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.
  2. DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring.
  3. SETD3 is a mechanosensitive enzyme that methylates actin on His-73 to regulate mitochondrial dynamics and function.
  4. Enhancing mitochondrial proteolysis alleviates alpha-synuclein-mediated cellular toxicity.
  5. Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia.
  6. A tripartite organelle platform links growth factor receptor signaling to mitochondrial metabolism.
  7. Olfaction regulates peripheral mitophagy and mitochondrial function.
  8. Alternative oxidase blunts pseudohypoxia and photoreceptor degeneration due to RPE mitochondrial dysfunction.
  9. Psychosocial experiences are associated with human brain mitochondrial biology.
  10. MFN2 coordinates mitochondria motility with α-tubulin acetylation and this regulation is disrupted in CMT2A.
  11. Mitochondria and cell death.
  12. Mitochondrial biology: Unique membrane remodeling from the matrix.
  13. Metabolic regulation of misfolded protein import into mitochondria.
  14. Oxidative protein folding in the intermembrane space of human mitochondria.
  15. The initiation of mitochondrial DNA replication.
  1. Dev Cell. 2024 May 20. pii: S1534-5807(24)00295-8. [Epub ahead of print]
    Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.
    George Kelly, Tetsushi Kataura, Johan Panek, Gailing Ma, Hanna Salmonowicz, Ashley Davis, Hannah Kendall, Charlotte Brookes, Daniel Moscoh Ayine-Tora, Peter Banks, Glyn Nelson, Laura Dobby, Patricia R Pitrez, Laura Booth, Lydia Costello, Gavin D Richardson, Penny Lovat, Stefan Przyborski, Lino Ferreira, Laura Greaves, Karolina Szczepanowska, Thomas von Zglinicki, Satomi Miwa, Max Brown, Michael Flagler, John E Oblong, Charles C Bascom, Bernadette Carroll, Jóhannes Reynisson, Viktor I Korolchuk.
      Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here, we demonstrated that primary human cells maintain highly active basal mitophagy initiated by mitochondrial superoxide signaling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor (SAR). Importantly, this pathway was suppressed upon the induction of cellular senescence and in naturally aged cells, leading to a robust shutdown of mitophagy. Inhibition of mitophagy in proliferating cells was sufficient to trigger the senescence program, while reactivation of mitophagy was necessary for the anti-senescence effects of NAD precursors or rapamycin. Furthermore, reactivation of mitophagy by a p62-targeting small molecule rescued markers of cellular aging, which establishes mitochondrial quality control as a promising target for anti-aging interventions.
    Keywords:  PINK1; Parkin; aging; autophagy; mitophagy; nicotinamide; nicotinamide riboside; p62; rapamycin; redox; senescence
    DOI:  https://doi.org/10.1016/j.devcel.2024.04.020
  2. Nat Commun. 2024 Jun 20. 15(1): 5265
    DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring.
    Adinarayana Marada, Corvin Walter, Tamara Suhm, Sahana Shankar, Arpita Nandy, Tilman Brummer, Ines Dhaouadi, F-Nora Vögtle, Chris Meisinger.
      Mitochondria require an extensive proteome to maintain a variety of metabolic reactions, and changes in cellular demand depend on rapid adaptation of the mitochondrial protein composition. The TOM complex, the organellar entry gate for mitochondrial precursors in the outer membrane, is a target for cytosolic kinases to modulate protein influx. DYRK1A phosphorylation of the carrier import receptor TOM70 at Ser91 enables its efficient docking and thus transfer of precursor proteins to the TOM complex. Here, we probe TOM70 phosphorylation in molecular detail and find that TOM70 is not a CK2 target nor import receptor for MIC19 as previously suggested. Instead, we identify TOM20 as a MIC19 import receptor and show off-target inhibition of the DYRK1A-TOM70 axis with the clinically used CK2 inhibitor CX4945 which activates TOM20-dependent import pathways. Taken together, modulation of DYRK1A signalling adapts the central mitochondrial protein entry gate via synchronization of TOM70- and TOM20-dependent import pathways for metabolic rewiring. Thus, DYRK1A emerges as a cytosolic surveillance kinase to regulate and fine-tune mitochondrial protein biogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-49611-4
  3. J Cell Sci. 2024 Jun 19. pii: jcs.261268. [Epub ahead of print]
    SETD3 is a mechanosensitive enzyme that methylates actin on His-73 to regulate mitochondrial dynamics and function.
    Vaibhav Deshmukh, James F Martin.
      Mitochondria, which act as sensors of metabolic homeostasis and metabolite signaling, form a dynamic intracellular network of continuously changing shape, size, and localization to respond to localized cellular energy demands. Mitochondrial dynamics and function depend on interactions with the F-actin cytoskeleton that are poorly understood. Here, we show that SET domain protein 3 (SETD3), a recently described actin histidine methyltransferase, directly methylates actin Histidine-73 and enhances F-actin polymerization on mitochondria. SETD3 is a mechano-sensitive enzyme which is localized on the outer mitochondrial membrane and promotes actin polymerization around mitochondrias. SETD3 loss of function leads to diminished F-actin around mitochondria and a decrease in mitochondrial branch length, branch number, and mitochondrial movement. Our functional analysis revealed that SETD3 is required for oxidative phosphorylation and mitochondrial complex I assembly, and function. Our data further indicate that SETD3 regulates F-actin formation around mitochondria and is essential for maintaining mitochondrial morphology, movement, and function. Finally, we discovered that SETD3 levels are regulated by ECM stiffness and regulate mitochondrial shape in response to changes in ECM stiffness. These findings provide new insight into the mechanism for F-actin polymerization around mitochondria.
    Keywords:  Cytoskeleton; Mechanotransduction; Mitochondrial dynamics; Post-translational modifications
    DOI:  https://doi.org/10.1242/jcs.261268
  4. NPJ Parkinsons Dis. 2024 Jun 21. 10(1): 120
    Enhancing mitochondrial proteolysis alleviates alpha-synuclein-mediated cellular toxicity.
    Xi Zhang, Linhao Ruan, Hu Wang, Jin Zhu, Taibo Li, Gordon Sun, Yi Dong, Yuhao Wang, Gil Berreby, Ashley Shay, Rong Chen, Sreekumar Ramachandran, Valina L Dawson, Ted M Dawson, Rong Li.
      Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing protein aggregates known as Lewy bodies (LB). Here, we investigated the entry of α-Syn into mitochondria to cause mitochondrial dysfunction and loss of cellular fitness in vivo. We show that α-Syn expressed in yeast and human cells is constitutively imported into mitochondria. In a transgenic mouse model, the level of endogenous α-Syn accumulation in mitochondria of dopaminergic neurons and microglia increases with age. The imported α-Syn is degraded by conserved mitochondrial proteases, most notably NLN and PITRM1 (Prd1 and Cym1 in yeast, respectively). α-Syn in the mitochondrial matrix that is not degraded interacts with respiratory chain complexes, leading to loss of mitochondrial DNA (mtDNA), mitochondrial membrane potential and cellular fitness decline. Importantly, enhancing mitochondrial proteolysis by increasing levels of specific proteases alleviated these defects in yeast, human cells, and a PD model of mouse primary neurons. Together, our results provide a direct link between α-synuclein-mediated cellular toxicity and its import into mitochondria and reveal potential therapeutic targets for the treatment of α-synucleinopathies.
    DOI:  https://doi.org/10.1038/s41531-024-00733-y
  5. Sci Transl Med. 2024 Jun 12. 16(751): eadi5336
    Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia.
    Ahmed Khalaf, Lucie de Beauchamp, Eric Kalkman, Kevin Rattigan, Ekaterini Himonas, Joe Jones, Daniel James, Engy Shokry Abd Shokry, Mary T Scott, Karen Dunn, Saverio Tardito, Mhairi Copland, David Sumpton, Emma Shanks, G Vignir Helgason.
      In chronic myeloid leukemia (CML), the persistence of leukemic stem cells (LSCs) after treatment with tyrosine kinase inhibitors (TKIs), such as imatinib, can lead to disease relapse. It is known that therapy-resistant LSCs rely on oxidative phosphorylation (OXPHOS) for their survival and that targeting mitochondrial respiration sensitizes CML LSCs to imatinib treatment. However, current OXPHOS inhibitors have demonstrated limited efficacy or have shown adverse effects in clinical trials, highlighting that identification of clinically safe oxidative pathway inhibitors is warranted. We performed a high-throughput drug repurposing screen designed to identify mitochondrial metabolism inhibitors in myeloid leukemia cells. This identified lomerizine, a US Food and Drug Administration (FDA)-approved voltage-gated Ca2+ channel blocker now used for the treatment of migraines, as one of the top hits. Transcriptome analysis revealed increased expression of voltage-gated CACNA1D and receptor-activated TRPC6 Ca2+ channels in CML LSCs (CD34+CD38-) compared with normal counterparts. This correlated with increased endoplasmic reticulum (ER) mass and increased ER and mitochondrial Ca2+ content in CML stem/progenitor cells. We demonstrate that lomerizine-mediated inhibition of Ca2+ uptake leads to ER and mitochondrial Ca2+ depletion, with similar effects seen after CACNA1D and TRPC6 knockdown. Through stable isotope-assisted metabolomics and functional assays, we observe that lomerizine treatment inhibits mitochondrial isocitrate dehydrogenase activity and mitochondrial oxidative metabolism and selectively sensitizes CML LSCs to imatinib treatment. In addition, combination treatment with imatinib and lomerizine reduced CML tumor burden, targeted CML LSCs, and extended survival in xenotransplantation model of human CML, suggesting this as a potential therapeutic strategy to prevent disease relapse in patients.
    DOI:  https://doi.org/10.1126/scitranslmed.adi5336
  6. Nat Commun. 2024 Jun 15. 15(1): 5119
    A tripartite organelle platform links growth factor receptor signaling to mitochondrial metabolism.
    Deborah Mesa, Elisa Barbieri, Andrea Raimondi, Stefano Freddi, Giorgia Miloro, Gorana Jendrisek, Giusi Caldieri, Micaela Quarto, Irene Schiano Lomoriello, Maria Grazia Malabarba, Arianna Bresci, Francesco Manetti, Federico Vernuccio, Hind Abdo, Giorgio Scita, Letizia Lanzetti, Dario Polli, Carlo Tacchetti, Paolo Pinton, Massimo Bonora, Pier Paolo Di Fiore, Sara Sigismund.
      One open question in the biology of growth factor receptors is how a quantitative input (i.e., ligand concentration) is decoded by the cell to produce specific response(s). Here, we show that an EGFR endocytic mechanism, non-clathrin endocytosis (NCE), which is activated only at high ligand concentrations and targets receptor to degradation, requires a tripartite organelle platform involving the plasma membrane (PM), endoplasmic reticulum (ER) and mitochondria. At these contact sites, EGFR-dependent, ER-generated Ca2+ oscillations are sensed by mitochondria, leading to increased metabolism and ATP production. Locally released ATP is required for cortical actin remodeling and EGFR-NCE vesicle fission. The same biochemical circuitry is also needed for an effector function of EGFR, i.e., collective motility. The multiorganelle signaling platform herein described mediates direct communication between EGFR signaling and mitochondrial metabolism, and is predicted to have a broad impact on cell physiology as it is activated by another growth factor receptor, HGFR/MET.
    DOI:  https://doi.org/10.1038/s41467-024-49543-z
  7. Sci Adv. 2024 Jun 21. 10(25): eadn0014
    Olfaction regulates peripheral mitophagy and mitochondrial function.
    Julian G Dishart, Corinne L Pender, Koning Shen, Hanlin Zhang, Megan Ly, Madison B Webb, Andrew Dillin.
      The central nervous system coordinates peripheral cellular stress responses, including the unfolded protein response of the mitochondria (UPRMT); however, the contexts for which this regulatory capability evolved are unknown. UPRMT is up-regulated upon pathogenic infection and in metabolic flux, and the olfactory nervous system has been shown to regulate pathogen resistance and peripheral metabolic activity. Therefore, we asked whether the olfactory nervous system in Caenorhabditis elegans controls the UPRMT cell nonautonomously. We found that silencing a single inhibitory olfactory neuron pair, AWC, led to robust induction of UPRMT and reduction of oxidative phosphorylation dependent on serotonin signaling and parkin-mediated mitophagy. Further, AWC ablation confers resistance to the pathogenic bacteria Pseudomonas aeruginosa partially dependent on the UPRMT transcription factor atfs-1 and fully dependent on mitophagy machinery. These data illustrate a role for the olfactory nervous system in regulating whole-organism mitochondrial dynamics, perhaps in preparation for postprandial metabolic stress or pathogenic infection.
    DOI:  https://doi.org/10.1126/sciadv.adn0014
  8. Proc Natl Acad Sci U S A. 2024 Jun 18. 121(25): e2402384121
    Alternative oxidase blunts pseudohypoxia and photoreceptor degeneration due to RPE mitochondrial dysfunction.
    Ming Chen, Yekai Wang, Roopa Dalal, Jianhai Du, Douglas Vollrath.
      Loss of mitochondrial electron transport complex (ETC) function in the retinal pigment epithelium (RPE) in vivo results in RPE dedifferentiation and progressive photoreceptor degeneration, and has been implicated in the pathogenesis of age-related macular degeneration. Xenogenic expression of alternative oxidases in mammalian cells and tissues mitigates phenotypes arising from some mitochondrial electron transport defects, but can exacerbate others. We expressed an alternative oxidase from Ciona intestinalis (AOX) in ETC-deficient murine RPE in vivo to assess the retinal consequences of stimulating coenzyme Q oxidation and respiration without ATP generation. RPE-restricted expression of AOX in this context is surprisingly beneficial. This focused intervention mitigates RPE mTORC1 activation, dedifferentiation, hypertrophy, stress marker expression, pseudohypoxia, and aerobic glycolysis. These RPE cell autonomous changes are accompanied by increased glucose delivery to photoreceptors with attendant improvements in photoreceptor structure and function. RPE-restricted AOX expression normalizes accumulated levels of succinate and 2-hydroxyglutarate in ETC-deficient RPE, and counteracts deficiencies in numerous neural retinal metabolites. These features can be attributed to the activation of mitochondrial inner membrane flavoproteins such as succinate dehydrogenase and proline dehydrogenase, and alleviation of inhibition of 2-oxyglutarate-dependent dioxygenases such as prolyl hydroxylases and epigenetic modifiers. Our work underscores the importance to outer retinal health of coenzyme Q oxidation in the RPE and identifies a metabolic network critical for photoreceptor survival in the context of RPE mitochondrial dysfunction.
    Keywords:  alternative oxidase; coenzyme Q; mitochondrial dysfunction; retinal pigment epithelium; succinate
    DOI:  https://doi.org/10.1073/pnas.2402384121
  9. Proc Natl Acad Sci U S A. 2024 Jul 02. 121(27): e2317673121
    Psychosocial experiences are associated with human brain mitochondrial biology.
    Caroline Trumpff, Anna S Monzel, Carmen Sandi, Vilas Menon, Hans-Ulrich Klein, Masashi Fujita, Annie Lee, Vladislav A Petyuk, Cheyenne Hurst, Duc M Duong, Nicholas T Seyfried, Aliza P Wingo, Thomas S Wingo, Yanling Wang, Madhav Thambisetty, Luigi Ferrucci, David A Bennett, Philip L De Jager, Martin Picard.
      Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal brain function relies on energy transformation by mitochondria oxidative phosphorylation (OxPhos). Two main lines of evidence position mitochondria both as targets and drivers of psychosocial experiences. On the one hand, chronic stress exposure and mood states may alter multiple aspects of mitochondrial biology; on the other hand, functional variations in mitochondrial OxPhos capacity may alter social behavior, stress reactivity, and mood. But are psychosocial exposures and subjective experiences linked to mitochondrial biology in the human brain? By combining longitudinal antemortem assessments of psychosocial factors with postmortem brain (dorsolateral prefrontal cortex) proteomics in older adults, we find that higher well-being is linked to greater abundance of the mitochondrial OxPhos machinery, whereas higher negative mood is linked to lower OxPhos protein content. Combined, positive and negative psychosocial factors explained 18 to 25% of the variance in the abundance of OxPhos complex I, the primary biochemical entry point that energizes brain mitochondria. Moreover, interrogating mitochondrial psychobiological associations in specific neuronal and nonneuronal brain cells with single-nucleus RNA sequencing (RNA-seq) revealed strong cell-type-specific associations for positive psychosocial experiences and mitochondria in glia but opposite associations in neurons. As a result, these "mind-mitochondria" associations were masked in bulk RNA-seq, highlighting the likely underestimation of true psychobiological effect sizes in bulk brain tissues. Thus, self-reported psychosocial experiences are linked to human brain mitochondrial phenotypes.
    Keywords:  mitochondria; proteome; psychosocial factors; single cell RNA-seq; transcriptome
    DOI:  https://doi.org/10.1073/pnas.2317673121
  10. iScience. 2024 Jun 21. 27(6): 109994
    MFN2 coordinates mitochondria motility with α-tubulin acetylation and this regulation is disrupted in CMT2A.
    Atul Kumar, Delfina Larrea, Maria Elena Pero, Paola Infante, Marilisa Conenna, Grace J Shin, Vincent Van Elias, Wesley B Grueber, Lucia Di Marcotullio, Estela Area-Gomez, Francesca Bartolini.
      Mitofusin-2 (MFN2), a large GTPase residing in the mitochondrial outer membrane and mutated in Charcot-Marie-Tooth type 2 disease (CMT2A), is a regulator of mitochondrial fusion and tethering with the ER. The role of MFN2 in mitochondrial transport has however remained elusive. Like MFN2, acetylated microtubules play key roles in mitochondria dynamics. Nevertheless, it is unknown if the α-tubulin acetylation cycle functionally interacts with MFN2. Here, we show that mitochondrial contacts with microtubules are sites of α-tubulin acetylation, which occurs through MFN2-mediated recruitment of α-tubulin acetyltransferase 1 (ATAT1). This activity is critical for MFN2-dependent regulation of mitochondria transport, and axonal degeneration caused by CMT2A MFN2 associated R94W and T105M mutations may depend on the inability to release ATAT1 at sites of mitochondrial contacts with microtubules. Our findings reveal a function for mitochondria in α-tubulin acetylation and suggest that disruption of this activity plays a role in the onset of MFN2-dependent CMT2A.
    Keywords:  Cell biology; Lipidomics; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109994
  11. Nat Cell Biol. 2024 Jun 20.
    Mitochondria and cell death.
    Hannah L Glover, Annabell Schreiner, Grant Dewson, Stephen W G Tait.
      Mitochondria are cellular factories for energy production, calcium homeostasis and iron metabolism, but they also have an unequivocal and central role in intrinsic apoptosis through the release of cytochrome c. While the subsequent activation of proteolytic caspases ensures that cell death proceeds in the absence of collateral inflammation, other phlogistic cell death pathways have been implicated in using, or engaging, mitochondria. Here we discuss the emerging complexities of intrinsic apoptosis controlled by the BCL-2 family of proteins. We highlight the emerging theory that non-lethal mitochondrial apoptotic signalling has diverse biological roles that impact cancer, innate immunity and ageing. Finally, we delineate the role of mitochondria in other forms of cell death, such as pyroptosis, ferroptosis and necroptosis, and discuss mitochondria as central hubs for the intersection and coordination of cell death signalling pathways, underscoring their potential for therapeutic manipulation.
    DOI:  https://doi.org/10.1038/s41556-024-01429-4
  12. Curr Biol. 2024 Jun 17. pii: S0960-9822(24)00608-0. [Epub ahead of print]34(12): R581-R583
    Mitochondrial biology: Unique membrane remodeling from the matrix.
    Jason A Mears.
      A new study reports the identification of a fission yeast dynamin superfamily protein, Mmc1, that self-assembles on the matrix side of the inner mitochondrial membrane and interacts with subunits of the mitochondrial contact site and cristae organizing system to maintain cristae architecture.
    DOI:  https://doi.org/10.1016/j.cub.2024.05.010
  13. Elife. 2024 Jun 20. pii: RP87518. [Epub ahead of print]12
    Metabolic regulation of misfolded protein import into mitochondria.
    Yuhao Wang, Linhao Ruan, Jin Zhu, Xi Zhang, Alexander Chih-Chieh Chang, Alexis Tomaszewski, Rong Li.
      Mitochondria are the cellular energy hub and central target of metabolic regulation. Mitochondria also facilitate proteostasis through pathways such as the 'mitochondria as guardian in cytosol' (MAGIC) whereby cytosolic misfolded proteins (MPs) are imported into and degraded inside mitochondria. In this study, a genome-wide screen in Saccharomyces cerevisiae uncovered that Snf1, the yeast AMP-activated protein kinase (AMPK), inhibits the import of MPs into mitochondria while promoting mitochondrial biogenesis under glucose starvation. We show that this inhibition requires a downstream transcription factor regulating mitochondrial gene expression and is likely to be conferred through substrate competition and mitochondrial import channel selectivity. We further show that Snf1/AMPK activation protects mitochondrial fitness in yeast and human cells under stress induced by MPs such as those associated with neurodegenerative diseases.
    Keywords:  AMPK; MAGIC; S. cerevisiae; cell biology; human; metabolism; misfolded protein; mitochondria; protein import; proteostasis
    DOI:  https://doi.org/10.7554/eLife.87518
  14. FEBS Open Bio. 2024 Jun 12.
    Oxidative protein folding in the intermembrane space of human mitochondria.
    Christine Zarges, Jan Riemer.
      The mitochondrial intermembrane space hosts a machinery for oxidative protein folding, the mitochondrial disulfide relay. This machinery imports a large number of soluble proteins into the compartment, where they are retained through oxidative folding. Additionally, the disulfide relay enhances the stability of many proteins by forming disulfide bonds. In this review, we describe the mitochondrial disulfide relay in human cells, its components, and their coordinated collaboration in mechanistic detail. We also discuss the human pathologies associated with defects in this machinery and its protein substrates, providing a comprehensive overview of its biological importance and implications for health.
    Keywords:  ALR; IMS; MIA40; mitochondria; oxidative protein folding; protein import
    DOI:  https://doi.org/10.1002/2211-5463.13839
  15. Biochem Soc Trans. 2024 Jun 17. pii: BST20230952. [Epub ahead of print]
    The initiation of mitochondrial DNA replication.
    Yi Liu, Haibin Liu, Fan Zhang, Hong Xu.
      Mitochondrial DNA replication is initiated by the transcription of mitochondrial RNA polymerase (mtRNAP), as mitochondria lack a dedicated primase. However, the mechanism determining the switch between continuous transcription and premature termination to generate RNA primers for mitochondrial DNA (mtDNA) replication remains unclear. The pentatricopeptide repeat domain of mtRNAP exhibits exoribonuclease activity, which is required for the initiation of mtDNA replication in Drosophila. In this review, we explain how this exonuclease activity contributes to primer synthesis in strand-coupled mtDNA replication, and discuss how its regulation might co-ordinate mtDNA replication and transcription in both Drosophila and mammals.
    Keywords:  PPR; RNA polymerase; exonucleases; mitochondria; mtDNA; replication
    DOI:  https://doi.org/10.1042/BST20230952
This page is being maintained by Thomas Krichel. It was last updated on 2024‒06‒25 at 16:15.