bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2023–03–12
seven papers selected by
Avinash N. Mukkala, University of Toronto
  1. Fumarate induces vesicular release of mtDNA to drive innate immunity.
  2. Transferred mitochondria accumulate reactive oxygen species, promoting proliferation.
  3. Real-Time Visualization of Cytosolic and Mitochondrial ATP Dynamics in Response to Metabolic Stress in Cultured Cells.
  4. Mitochondrial molecule controls inflammation.
  5. Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.
  6. ATP synthase interactome analysis identifies a new subunit l as a modulator of permeability transition pore in yeast.
  7. Plasma cell derived mtDAMPs activate macrophage STING pathway which promotes myeloma progression.
  1. Nature. 2023 Mar 08.
    Fumarate induces vesicular release of mtDNA to drive innate immunity.
    Vincent Zecchini, Vincent Paupe, Irene Herranz-Montoya, Joëlle Janssen, Inge M N Wortel, Jordan L Morris, Ashley Ferguson, Suvagata Roy Chowdury, Marc Segarra-Mondejar, Ana S H Costa, Gonçalo C Pereira, Laura Tronci, Timothy Young, Efterpi Nikitopoulou, Ming Yang, Dóra Bihary, Federico Caicci, Shun Nagashima, Alyson Speed, Kalliopi Bokea, Zara Baig, Shamith Samarajiwa, Maxine Tran, Thomas Mitchell, Mark Johnson, Julien Prudent, Christian Frezza.
      Mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma1. Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate2. However, although the long-term consequences of FH loss have been described, the acute response has not so far been investigated. Here we generated an inducible mouse model to study the chronology of FH loss in the kidney. We show that loss of FH leads to early alterations of mitochondrial morphology and the release of mitochondrial DNA (mtDNA) into the cytosol, where it triggers the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1) pathway and stimulates an inflammatory response that is also partially dependent on retinoic-acid-inducible gene I (RIG-I). Mechanistically, we show that this phenotype is mediated by fumarate and occurs selectively through mitochondrial-derived vesicles in a manner that depends on sorting nexin 9 (SNX9). These results reveal that increased levels of intracellular fumarate induce a remodelling of the mitochondrial network and the generation of mitochondrial-derived vesicles, which allows the release of mtDNAin the cytosol and subsequent activation of the innate immune response.
    DOI:  https://doi.org/10.1038/s41586-023-05770-w
  2. Elife. 2023 Mar 06. pii: e85494. [Epub ahead of print]12
    Transferred mitochondria accumulate reactive oxygen species, promoting proliferation.
    Chelsea U Kidwell, Joseph R Casalini, Soorya Pradeep, Sandra D Scherer, Daniel Greiner, Defne Bayik, Dionysios C Watson, Gregory S Olson, Justin D Lathia, Jarrod S Johnson, Jared Rutter, Alana L Welm, Thomas A Zangle, Minna Roh-Johnson.
      Recent studies reveal that lateral mitochondrial transfer, the movement of mitochondria from one cell to another, can affect cellular and tissue homeostasis1,2. Most of what we know about mitochondrial transfer stems from bulk cell studies and have led to the paradigm that functional transferred mitochondria restore bioenergetics and revitalize cellular functions to recipient cells with damaged or non-functional mitochondrial networks3. However, we show that mitochondrial transfer also occurs between cells with functioning endogenous mitochondrial networks, but the mechanisms underlying how transferred mitochondria can promote such sustained behavioral reprogramming remain unclear. We report that unexpectedly, transferred macrophage mitochondria are dysfunctional and accumulate reactive oxygen species in recipient cancer cells. We further discovered that reactive oxygen species accumulation activates ERK signaling, promoting cancer cell proliferation. Pro-tumorigenic macrophages exhibit fragmented mitochondrial networks, leading to higher rates of mitochondrial transfer to cancer cells. Finally, we observe that macrophage mitochondrial transfer promotes tumor cell proliferation in vivo. Collectively these results indicate that transferred macrophage mitochondria activate downstream signaling pathways in a ROS-dependent manner in cancer cells, and provide a model of how sustained behavioral reprogramming can be mediated by a relatively small amount of transferred mitochondria in vitro and in vivo.
    Keywords:  cancer biology; cell biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.85494
  3. Cells. 2023 Feb 22. pii: 695. [Epub ahead of print]12(5):
    Real-Time Visualization of Cytosolic and Mitochondrial ATP Dynamics in Response to Metabolic Stress in Cultured Cells.
    Donnell White, Lothar Lauterboeck, Parnia Mobasheran, Tetsuya Kitaguchi, Antoine H Chaanine, Qinglin Yang.
      Adenosine 5' triphosphate (ATP) is the energy currency of life, which is produced in mitochondria (~90%) and cytosol (less than 10%). Real-time effects of metabolic changes on cellular ATP dynamics remain indeterminate. Here we report the design and validation of a genetically encoded fluorescent ATP indicator that allows for real-time, simultaneous visualization of cytosolic and mitochondrial ATP in cultured cells. This dual-ATP indicator, called smacATPi (simultaneous mitochondrial and cytosolic ATP indicator), combines previously described individual cytosolic and mitochondrial ATP indicators. The use of smacATPi can help answer biological questions regarding ATP contents and dynamics in living cells. As expected, 2-deoxyglucose (2-DG, a glycolytic inhibitor) led to substantially decreased cytosolic ATP, and oligomycin (a complex V inhibitor) markedly decreased mitochondrial ATP in cultured HEK293T cells transfected with smacATPi. With the use of smacATPi, we can also observe that 2-DG treatment modestly attenuates mitochondrial ATP and oligomycin reduces cytosolic ATP, indicating the subsequent changes of compartmental ATP. To evaluate the role of ATP/ADP carrier (AAC) in ATP trafficking, we treated HEK293T cells with an AAC inhibitor, Atractyloside (ATR). ATR treatment attenuated cytosolic and mitochondrial ATP in normoxia, suggesting AAC inhibition reduces ADP import from the cytosol to mitochondria and ATP export from mitochondria to cytosol. In HEK293T cells subjected to hypoxia, ATR treatment increased mitochondrial ATP along with decreased cytosolic ATP, implicating that ACC inhibition during hypoxia sustains mitochondrial ATP but may not inhibit the reversed ATP import from the cytosol. Furthermore, both mitochondrial and cytosolic signals decrease when ATR is given in conjunction with 2-DG in hypoxia. Thus, real-time visualization of spatiotemporal ATP dynamics using smacATPi provides novel insights into how cytosolic and mitochondrial ATP signals respond to metabolic changes, providing a better understanding of cellular metabolism in health and disease.
    Keywords:  ATP; biosensor; fluorescence; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/cells12050695
  4. Nature. 2023 Mar 08.
    Mitochondrial molecule controls inflammation.
    Taylor A Poor, Navdeep S Chandel.
      
    Keywords:  Cell biology; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-00596-y
  5. Nature. 2023 Mar 08.
    Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.
    Alexander Hooftman, Christian G Peace, Dylan G Ryan, Emily A Day, Ming Yang, Anne F McGettrick, Maureen Yin, Erica N Montano, Lihong Huo, Juliana E Toller-Kawahisa, Vincent Zecchini, Tristram A J Ryan, Alfonso Bolado-Carrancio, Alva M Casey, Hiran A Prag, Ana S H Costa, Gabriela De Los Santos, Mariko Ishimori, Daniel J Wallace, Swamy Venuturupalli, Efterpi Nikitopoulou, Norma Frizzell, Cecilia Johansson, Alexander Von Kriegsheim, Michael P Murphy, Caroline Jefferies, Christian Frezza, Luke A J O'Neill.
      Metabolic rewiring underlies the effector functions of macrophages1-3, but the mechanisms involved remain incompletely defined. Here, using unbiased metabolomics and stable isotope-assisted tracing, we show that an inflammatory aspartate-argininosuccinate shunt is induced following lipopolysaccharide stimulation. The shunt, supported by increased argininosuccinate synthase (ASS1) expression, also leads to increased cytosolic fumarate levels and fumarate-mediated protein succination. Pharmacological inhibition and genetic ablation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) further increases intracellular fumarate levels. Mitochondrial respiration is also suppressed and mitochondrial membrane potential increased. RNA sequencing and proteomics analyses demonstrate that there are strong inflammatory effects resulting from FH inhibition. Notably, acute FH inhibition suppresses interleukin-10 expression, which leads to increased tumour necrosis factor secretion, an effect recapitulated by fumarate esters. Moreover, FH inhibition, but not fumarate esters, increases interferon-β production through mechanisms that are driven by mitochondrial RNA (mtRNA) release and activation of the RNA sensors TLR7, RIG-I and MDA5. This effect is recapitulated endogenously when FH is suppressed following prolonged lipopolysaccharide stimulation. Furthermore, cells from patients with systemic lupus erythematosus also exhibit FH suppression, which indicates a potential pathogenic role for this process in human disease. We therefore identify a protective role for FH in maintaining appropriate macrophage cytokine and interferon responses.
    DOI:  https://doi.org/10.1038/s41586-023-05720-6
  6. Sci Rep. 2023 Mar 07. 13(1): 3839
    ATP synthase interactome analysis identifies a new subunit l as a modulator of permeability transition pore in yeast.
    Chiranjit Panja, Aneta Wiesyk, Katarzyna Niedźwiecka, Emilia Baranowska, Roza Kucharczyk.
      The mitochondrial ATP synthase, an enzyme that synthesizes ATP and is involved in the formation of the mitochondrial mega-channel and permeability transition, is a multi-subunit complex. In S. cerevisiae, the uncharacterized protein Mco10 was previously found to be associated with ATP synthase and referred as a new 'subunit l'. However, recent cryo-EM structures could not ascertain Mco10 with the enzyme making questionable its role as a structural subunit. The N-terminal part of Mco10 is very similar to k/Atp19 subunit, which along with subunits g/Atp20 and e/Atp21 plays a major role in stabilization of the ATP synthase dimers. In our effort to confidently define the small protein interactome of ATP synthase we found Mco10. We herein investigate the impact of Mco10 on ATP synthase functioning. Biochemical analysis reveal in spite of similarity in sequence and evolutionary lineage, that Mco10 and Atp19 differ significantly in function. The Mco10 is an auxiliary ATP synthase subunit that only functions in permeability transition.
    DOI:  https://doi.org/10.1038/s41598-023-30966-5
  7. Blood. 2023 Mar 08. pii: blood.2022018711. [Epub ahead of print]
    Plasma cell derived mtDAMPs activate macrophage STING pathway which promotes myeloma progression.
    Aisha Jibril, Charlotte Hellmich, Edyta Wojtowicz, Katherine Hampton, Rebecca S Maynard, Ravindu De Silva, Dominic J Fowler-Shorten, Jayna J Mistry, Jamie A Moore, Kristian M Bowles, Stuart A Rushworth.
      Mitochondrial damage-associated molecular patterns (mtDAMPs) include proteins, lipids, metabolites and DNA and have various context specific immunoregulatory functions. Cell-free mitochondrial DNA (mtDNA) is recognised via pattern recognition receptors and is a potent activator of the innate immune system. Cell-free mtDNA is elevated in the circulation of trauma and cancer patients, however the functional consequences of elevated mtDNA are largely undefined. Multiple myeloma (MM) relies upon cellular interactions within the bone marrow (BM) microenvironment for survival and progression. Here, using in-vivo models, we describe the role of MM cell derived mtDAMPs in the pro-tumoral BM microenvironment, and the mechanism and functional consequence of mtDAMPs in myeloma disease progression. Initially, we identified elevated levels of mtDNA in the peripheral blood serum of MM patients compared to healthy controls. Using the MM1S cells engrafted into NSG mice we established that elevated mtDNA was derived from MM cells. We further show that BM macrophages sense and respond to mtDAMPs through the STING pathway and inhibition of this pathway reduces MM tumor-burden in the KaLwRij-5TGM1 mouse model. Moreover, we found that MM derived mtDAMPs induced upregulation of chemokine signatures in BM macrophages and inhibition of this signature resulted in egress of MM cells from the BM. Here, we demonstrate that malignant plasma cells release mtDNA, a form of mtDAMPs, into the myeloma BM microenvironment, which in turn activates macrophages via STING signalling. We establish the functional role of these mtDAMP-activated macrophages in promoting disease progression and retaining MM cells in the pro-tumoral BM microenvironment.
    DOI:  https://doi.org/10.1182/blood.2022018711
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