bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024‒03‒31
ten papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis.
  2. Force-induced tail-autotomy mitochondrial fission and biogenesis of matrix-excluded mitochondrial-derived vesicles for quality control.
  3. OMA1 protease eliminates arrested protein import intermediates upon mitochondrial depolarization.
  4. Mitochondrial H2O2 release does not directly cause damage to chromosomal DNA.
  5. Defective mitochondria remodelling in B cells leads to an aged immune response.
  6. Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress.
  7. Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations.
  8. Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species.
  9. A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders.
  10. Tumour immunogenicity goes with the (mitochondrial electron) flow.
  1. Science. 2024 Mar 29. 383(6690): 1484-1492
    Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis.
    Umakant Sahu, Elodie Villa, Colleen R Reczek, Zibo Zhao, Brendan P O'Hara, Michael D Torno, Rohan Mishra, William D Shannon, John M Asara, Peng Gao, Ali Shilatifard, Navdeep S Chandel, Issam Ben-Sahra.
      Cellular purines, particularly adenosine 5'-triphosphate (ATP), fuel many metabolic reactions, but less is known about the direct effects of pyrimidines on cellular metabolism. We found that pyrimidines, but not purines, maintain pyruvate oxidation and the tricarboxylic citric acid (TCA) cycle by regulating pyruvate dehydrogenase (PDH) activity. PDH activity requires sufficient substrates and cofactors, including thiamine pyrophosphate (TPP). Depletion of cellular pyrimidines decreased TPP synthesis, a reaction carried out by TPP kinase 1 (TPK1), which reportedly uses ATP to phosphorylate thiamine (vitamin B1). We found that uridine 5'-triphosphate (UTP) acts as the preferred substrate for TPK1, enabling cellular TPP synthesis, PDH activity, TCA-cycle activity, lipogenesis, and adipocyte differentiation. Thus, UTP is required for vitamin B1 utilization to maintain pyruvate oxidation and lipogenesis.
    DOI:  https://doi.org/10.1126/science.adh2771
  2. Proc Natl Acad Sci U S A. 2024 Apr 02. 121(14): e2217019121
    Force-induced tail-autotomy mitochondrial fission and biogenesis of matrix-excluded mitochondrial-derived vesicles for quality control.
    Xiaoying Liu, Linyu Xu, Yutong Song, Zhihao Zhao, Xinyu Li, Cheuk-Yiu Wong, Rong Chen, Jianxiong Feng, Yitao Gou, Yajing Qi, Hei-Man Chow, Shuhuai Yao, Yi Wang, Song Gao, Xingguo Liu, Liting Duan.
      Mitochondria constantly fuse and divide for mitochondrial inheritance and functions. Here, we identified a distinct type of naturally occurring fission, tail-autotomy fission, wherein a tail-like thin tubule protrudes from the mitochondrial body and disconnects, resembling autotomy. Next, utilizing an optogenetic mitochondria-specific mechanostimulator, we revealed that mechanical tensile force drives tail-autotomy fission. This force-induced fission involves DRP1/MFF and endoplasmic reticulum tubule wrapping. It redistributes mitochondrial DNA, producing mitochondrial fragments with or without mitochondrial DNA for different fates. Moreover, tensile force can decouple outer and inner mitochondrial membranes, pulling out matrix-excluded tubule segments. Subsequent tail-autotomy fission separates the matrix-excluded tubule segments into matrix-excluded mitochondrial-derived vesicles (MDVs) which recruit Parkin and LC3B, indicating the unique role of tail-autotomy fission in segregating only outer membrane components for mitophagy. Sustained force promotes fission and MDV biogenesis more effectively than transient one. Our results uncover a mechanistically and functionally distinct type of fission and unveil the role of tensile forces in modulating fission and MDV biogenesis for quality control, underscoring the heterogeneity of fission and mechanoregulation of mitochondrial dynamics.
    Keywords:  mitochondrial fission; mitochondrial quality control; optogenetics; photoactivatable proteins; tensile force
    DOI:  https://doi.org/10.1073/pnas.2217019121
  3. J Cell Biol. 2024 May 06. pii: e202306051. [Epub ahead of print]223(5):
    OMA1 protease eliminates arrested protein import intermediates upon mitochondrial depolarization.
    Magda Krakowczyk, Anna M Lenkiewicz, Tomasz Sitarz, Dominika Malinska, Mayra Borrero, Ben Hur Marins Mussulini, Vanessa Linke, Andrzej A Szczepankiewicz, Joanna M Biazik, Agata Wydrych, Hanna Nieznanska, Remigiusz A Serwa, Agnieszka Chacinska, Piotr Bragoszewski.
      Most mitochondrial proteins originate from the cytosol and require transport into the organelle. Such precursor proteins must be unfolded to pass through translocation channels in mitochondrial membranes. Misfolding of transported proteins can result in their arrest and translocation failure. Arrested proteins block further import, disturbing mitochondrial functions and cellular proteostasis. Cellular responses to translocation failure have been defined in yeast. We developed the cell line-based translocase clogging model to discover molecular mechanisms that resolve failed import events in humans. The mechanism we uncover differs significantly from these described in fungi, where ATPase-driven extraction of blocked protein is directly coupled with proteasomal processing. We found human cells to rely primarily on mitochondrial factors to clear translocation channel blockage. The mitochondrial membrane depolarization triggered proteolytic cleavage of the stalled protein, which involved mitochondrial protease OMA1. The cleavage allowed releasing the protein fragment that blocked the translocase. The released fragment was further cleared in the cytosol by VCP/p97 and the proteasome.
    DOI:  https://doi.org/10.1083/jcb.202306051
  4. Nat Commun. 2024 Mar 28. 15(1): 2725
    Mitochondrial H2O2 release does not directly cause damage to chromosomal DNA.
    Daan M K van Soest, Paulien E Polderman, Wytze T F den Toom, Janneke P Keijer, Markus J van Roosmalen, Tim M F Leyten, Johannes Lehmann, Susan Zwakenberg, Sasha De Henau, Ruben van Boxtel, Boudewijn M T Burgering, Tobias B Dansen.
      Reactive Oxygen Species (ROS) derived from mitochondrial respiration are frequently cited as a major source of chromosomal DNA mutations that contribute to cancer development and aging. However, experimental evidence showing that ROS released by mitochondria can directly damage nuclear DNA is largely lacking. In this study, we investigated the effects of H2O2 released by mitochondria or produced at the nucleosomes using a titratable chemogenetic approach. This enabled us to precisely investigate to what extent DNA damage occurs downstream of near- and supraphysiological amounts of localized H2O2. Nuclear H2O2 gives rise to DNA damage and mutations and a subsequent p53 dependent cell cycle arrest. Mitochondrial H2O2 release shows none of these effects, even at levels that are orders of magnitude higher than what mitochondria normally produce. We conclude that H2O2 released from mitochondria is unlikely to directly damage nuclear genomic DNA, limiting its contribution to oncogenic transformation and aging.
    DOI:  https://doi.org/10.1038/s41467-024-47008-x
  5. Nat Commun. 2024 Mar 22. 15(1): 2569
    Defective mitochondria remodelling in B cells leads to an aged immune response.
    Marta Iborra-Pernichi, Jonathan Ruiz García, María Velasco de la Esperanza, Belén S Estrada, Elena R Bovolenta, Claudia Cifuentes, Cristina Prieto Carro, Tamara González Martínez, José García-Consuegra, María Fernanda Rey-Stolle, Francisco Javier Rupérez, Milagros Guerra Rodriguez, Rafael J Argüello, Sara Cogliati, Fernando Martín-Belmonte, Nuria Martínez-Martín.
      The B cell response in the germinal centre (GC) reaction requires a unique bioenergetic supply. Although mitochondria are remodelled upon antigen-mediated B cell receptor stimulation, mitochondrial function in B cells is still poorly understood. To gain a better understanding of the role of mitochondria in B cell function, here we generate mice with B cell-specific deficiency in Tfam, a transcription factor necessary for mitochondrial biogenesis. Tfam conditional knock-out (KO) mice display a blockage of the GC reaction and a bias of B cell differentiation towards memory B cells and aged-related B cells, hallmarks of an aged immune response. Unexpectedly, blocked GC reaction in Tfam KO mice is not caused by defects in the bioenergetic supply but is associated with a defect in the remodelling of the lysosomal compartment in B cells. Our results may thus describe a mitochondrial function for lysosome regulation and the downstream antigen presentation in B cells during the GC reaction, the dysruption of which is manifested as an aged immune response.
    DOI:  https://doi.org/10.1038/s41467-024-46763-1
  6. Cell Rep. 2024 Mar 28. pii: S2211-1247(24)00346-2. [Epub ahead of print]43(4): 114018
    Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress.
    Lea Bertgen, Jan-Eric Bökenkamp, Tim Schneckmann, Christian Koch, Markus Räschle, Zuzana Storchová, Johannes M Herrmann.
      Mitochondria consist of hundreds of proteins, most of which are inaccessible to the proteasomal quality control system of the cytosol. How cells stabilize the mitochondrial proteome during challenging conditions remains poorly understood. Here, we show that mitochondria form spatially defined protein aggregates as a stress-protecting mechanism. Two different types of intramitochondrial protein aggregates can be distinguished. The mitoribosomal protein Var1 (uS3m) undergoes a stress-induced transition from a soluble, chaperone-stabilized protein that is prevalent under benign conditions to an insoluble, aggregated form upon acute stress. The formation of Var1 bodies stabilizes mitochondrial proteostasis, presumably by sequestration of aggregation-prone proteins. The AAA chaperone Hsp78 is part of a second type of intramitochondrial aggregate that transiently sequesters proteins and promotes their folding or Pim1-mediated degradation. Thus, mitochondrial proteins actively control the formation of distinct types of intramitochondrial protein aggregates, which cooperate to stabilize the mitochondrial proteome during proteotoxic stress conditions.
    Keywords:  CP: Cell biology; CP: Molecular biology; Hsp78; MitoStores; Pim1 protease; Var1 bodies; aggregates; chaperones; mitochondria; mitoribosome; protein folding; protein import
    DOI:  https://doi.org/10.1016/j.celrep.2024.114018
  7. Mol Biol Cell. 2024 Mar 27. mbcE24010041
    Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations.
    Nicole Madrazo, Zinia Khattar, Evan T Powers, Jessica D Rosarda, R Luke Wiseman.
      Imbalances in mitochondrial proteostasis are associated with pathologic mitochondrial dysfunction implicated in etiologically-diverse diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria in response to mitochondrial stress. Numerous stress-responsive signaling pathways have been suggested to regulate mitochondria in response to proteotoxic stress. These include the integrated stress response (ISR), the heat shock response (HSR), and the oxidative stress response (OSR). Here, we define the stress signaling pathways activated in response to chronic mitochondrial proteostasis perturbations by monitoring the expression of sets of genes regulated downstream of each of these signaling pathways in published Perturb-seq datasets from K562 cells CRISPRi-depleted of mitochondrial proteostasis factors. Interestingly, we find that the ISR is preferentially activated in response to chronic, genetically-induced mitochondrial proteostasis stress, with no other pathway showing significant activation. Further, we demonstrate that CRISPRi depletion of other mitochondria-localized proteins similarly shows preferential activation of the ISR relative to other stress-responsive signaling pathways. These results both establish our gene set profiling approach as a viable strategy to probe stress responsive signaling pathways induced by perturbations to specific organelles and identify the ISR as the predominant stress-responsive signaling pathway activated in response to chronically disrupted of mitochondrial proteostasis.
    DOI:  https://doi.org/10.1091/mbc.E24-01-0041
  8. Cell Death Differ. 2024 Mar 22.
    Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species.
    Shun-Ichi Yamashita, Yuki Sugiura, Yuta Matsuoka, Rae Maeda, Keiichi Inoue, Kentaro Furukawa, Tomoyuki Fukuda, David C Chan, Tomotake Kanki.
      Mitophagy plays an important role in the maintenance of mitochondrial homeostasis and can be categorized into two types: ubiquitin-mediated and receptor-mediated pathways. During receptor-mediated mitophagy, mitophagy receptors facilitate mitophagy by tethering the isolation membrane to mitochondria. Although at least five outer mitochondrial membrane proteins have been identified as mitophagy receptors, their individual contribution and interrelationship remain unclear. Here, we show that HeLa cells lacking BNIP3 and NIX, two of the five receptors, exhibit a complete loss of mitophagy in various conditions. Conversely, cells deficient in the other three receptors show normal mitophagy. Using BNIP3/NIX double knockout (DKO) cells as a model, we reveal that mitophagy deficiency elevates mitochondrial reactive oxygen species (mtROS), which leads to activation of the Nrf2 antioxidant pathway. Notably, BNIP3/NIX DKO cells are highly sensitive to ferroptosis when Nrf2-driven antioxidant enzymes are compromised. Moreover, the sensitivity of BNIP3/NIX DKO cells is fully rescued upon the introduction of wild-type BNIP3 and NIX, but not the mutant forms incapable of facilitating mitophagy. Consequently, our results demonstrate that BNIP3 and NIX-mediated mitophagy plays a role in regulating mtROS levels and protects cells from ferroptosis.
    DOI:  https://doi.org/10.1038/s41418-024-01280-y
  9. Biochim Biophys Acta Mol Basis Dis. 2024 Mar 21. pii: S0925-4439(24)00120-0. [Epub ahead of print] 167131
    A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders.
    Amy E Vincent, Chun Chen, Tiago Bernardino Gomes, Valeria Di Leo, Tuomas Laalo, Kamil Pabis, Rodrick Capaldi, Michael F Marusich, David McDonald, Andrew Filby, Andrew Fuller, Diana Lehmann Urban, Stephan Zierz, Marcus Deschauer, Doug Turnbull, Amy K Reeve, Conor Lawless.
      Mitochondrial DNA (mtDNA) deletions which clonally expand in skeletal muscle of patients with mtDNA maintenance disorders, impair mitochondrial oxidative phosphorylation dysfunction. Previously we have shown that these mtDNA deletions arise and accumulate in perinuclear mitochondria causing localised mitochondrial dysfunction before spreading through the muscle fibre. We believe that mito-nuclear signalling is a key contributor in the accumulation and spread of mtDNA deletions, and that knowledge of how muscle fibres respond to mitochondrial dysfunction is key to our understanding of disease mechanisms. To understand the contribution of mito-nuclear signalling to the spread of mitochondrial dysfunction, we use imaging mass cytometry. We characterise the levels of mitochondrial Oxidative Phosphorylation proteins alongside a mitochondrial mass marker, in a cohort of patients with mtDNA maintenance disorders. Our expanded panel included protein markers of key signalling pathways, allowing us to investigate cellular responses to different combinations of oxidative phosphorylation dysfunction and ragged red fibres. We find combined Complex I and IV deficiency to be most common. Interestingly, in fibres deficient for one or more complexes, the remaining complexes are often upregulated beyond the increase of mitochondrial mass typically observed in ragged red fibres. We further find that oxidative phosphorylation deficient fibres exhibit an increase in the abundance of proteins involved in proteostasis, e.g. HSP60 and LONP1, and regulation of mitochondrial metabolism (including oxidative phosphorylation and proteolysis, e.g. PHB1). Our analysis suggests that the cellular response to mitochondrial dysfunction changes depending on the combination of deficient oxidative phosphorylation complexes in each fibre.
    Keywords:  Cell signalling; Mitochondrial DNA deletion; Mitochondrial disease; Myopathy; OXPHOS
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167131
  10. Mol Oncol. 2024 Mar 22.
    Tumour immunogenicity goes with the (mitochondrial electron) flow.
    Asma Ahmed, Stephen W G Tait.
      Mitochondrial metabolism and electron transport chain (ETC) function are essential for tumour proliferation and metastasis. However, the impact of ETC function on cancer immunogenicity is not well understood. In a recent study, Mangalhara et al. found that inhibition of complex II leads to enhanced tumour immunogenicity, T-cell-mediated cytotoxicity and inhibition of tumour growth. Surprisingly, this antitumour effect is mediated by succinate accumulation affecting histone methylation. Histone methylation promotes the transcriptional upregulation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes in a manner independent of interferon signalling. Modulating mitochondrial electron flow to enhance tumour immunogenicity provides an exciting new therapeutic avenue and may be particularly attractive for tumours with reduced expression of MHC-APP genes or dampened interferon signalling.
    Keywords:  complex II; electron transport chain; major histocompatibility complex class I; succinate
    DOI:  https://doi.org/10.1002/1878-0261.13627
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