bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024–04–07
eleven papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Ancestral allele of DNA polymerase gamma modifies antiviral tolerance.
  2. Mitochondrial injury induced by a Salmonella genotoxin triggers the proinflammatory senescence-associated secretory phenotype.
  3. Membrane fission via transmembrane contact.
  4. The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.
  5. Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies.
  6. Cytosolic retention of HtrA2 during mitochondrial protein import stress triggers the DELE1-HRI pathway.
  7. Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.
  8. Role of the mitochondrial protein cyclophilin D in skin wound healing and collagen.
  9. PINK1 deficiency alters muscle stem cell fate decision and muscle regenerative capacity.
  10. Identification and structural characterization of small molecule inhibitors of PINK1.
  11. Structural mechanisms of mitochondrial uncoupling protein 1 regulation in thermogenesis.
  1. Nature. 2024 Apr 03.
    Ancestral allele of DNA polymerase gamma modifies antiviral tolerance.
    Yilin Kang, Jussi Hepojoki, Rocio Sartori Maldonado, Takayuki Mito, Mügen Terzioglu, Tuula Manninen, Ravi Kant, Sachin Singh, Alaa Othman, Rohit Verma, Johanna Uusimaa, Kirmo Wartiovaara, Lauri Kareinen, Nicola Zamboni, Tuula Anneli Nyman, Anders Paetau, Anja Kipar, Olli Vapalahti, Anu Suomalainen.
      Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response1-4. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1)5. Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms5, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals6 demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism.
    DOI:  https://doi.org/10.1038/s41586-024-07260-z
  2. Nat Commun. 2024 Mar 30. 15(1): 2778
    Mitochondrial injury induced by a Salmonella genotoxin triggers the proinflammatory senescence-associated secretory phenotype.
    Han-Yi Chen, Wan-Chen Hsieh, Yu-Chieh Liu, Huei-Ying Li, Po-Yo Liu, Yu-Ting Hsu, Shao-Chun Hsu, An-Chi Luo, Wei-Chen Kuo, Yi-Jhen Huang, Gan-Guang Liou, Meng-Yun Lin, Chun-Jung Ko, Hsing-Chen Tsai, Shu-Jung Chang.
      Bacterial genotoxins damage host cells by targeting their chromosomal DNA. In the present study, we demonstrate that a genotoxin of Salmonella Typhi, typhoid toxin, triggers the senescence-associated secretory phenotype (SASP) by damaging mitochondrial DNA. The actions of typhoid toxin disrupt mitochondrial DNA integrity, leading to mitochondrial dysfunction and disturbance of redox homeostasis. Consequently, it facilitates the release of damaged mitochondrial DNA into the cytosol, activating type I interferon via the cGAS-STING pathway. We also reveal that the GCN2-mediated integrated stress response plays a role in the upregulation of inflammatory components depending on the STING signaling axis. These SASP factors can propagate the senescence effect on T cells, leading to senescence in these cells. These findings provide insights into how a bacterial genotoxin targets mitochondria to trigger a proinflammatory SASP, highlighting a potential therapeutic target for an anti-toxin intervention.
    DOI:  https://doi.org/10.1038/s41467-024-47190-y
  3. Nat Commun. 2024 Mar 30. 15(1): 2793
    Membrane fission via transmembrane contact.
    Russell K W Spencer, Isaac Santos-Pérez, Izaro Rodríguez-Renovales, Juan Manuel Martinez Galvez, Anna V Shnyrova, Marcus Müller.
      Division of intracellular organelles often correlates with additional membrane wrapping, e.g., by the endoplasmic reticulum or the outer mitochondrial membrane. Such wrapping plays a vital role in proteome and lipidome organization. However, how an extra membrane impacts the mechanics of the division has not been investigated. Here we combine fluorescence and cryo-electron microscopy experiments with self-consistent field theory to explore the stress-induced instabilities imposed by membrane wrapping in a simple double-membrane tubular system. We find that, at physiologically relevant conditions, the outer membrane facilitates an alternative pathway for the inner-tube fission through the formation of a transient contact (hemi-fusion) between both membranes. A detailed molecular theory of the fission pathways in the double membrane system reveals the topological complexity of the process, resulting both in leaky and leakless intermediates, with energies and topologies predicting physiological events.
    DOI:  https://doi.org/10.1038/s41467-024-47122-w
  4. EMBO Rep. 2024 Apr 02.
    The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.
    Christian Koch, Svenja Lenhard, Markus Räschle, Cristina Prescianotto-Baschong, Anne Spang, Johannes M Herrmann.
      Most mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria in a post-translational reaction. Mitochondrial precursor proteins which use the ER-SURF pathway employ the surface of the endoplasmic reticulum (ER) as an important sorting platform. How they reach the mitochondrial import machinery from the ER is not known. Here we show that mitochondrial contact sites play a crucial role in the ER-to-mitochondria transfer of precursor proteins. The ER mitochondria encounter structure (ERMES) and Tom70, together with Djp1 and Lam6, are part of two parallel and partially redundant ER-to-mitochondria delivery routes. When ER-to-mitochondria transfer is prevented by loss of these two contact sites, many precursors of mitochondrial inner membrane proteins are left stranded on the ER membrane, resulting in mitochondrial dysfunction. Our observations support an active role of the ER in mitochondrial protein biogenesis.
    Keywords:  Contact sites; ERMES; Endoplasmic reticulum; Mitochondria; Protein import
    DOI:  https://doi.org/10.1038/s44319-024-00113-w
  5. Nat Commun. 2024 Mar 30. 15(1): 2803
    Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies.
    Saeed Daneshmandi, Jee Eun Choi, Qi Yan, Cameron R MacDonald, Manu Pandey, Mounika Goruganthu, Nathan Roberts, Prashant K Singh, Richard M Higashi, Andrew N Lane, Teresa W-M Fan, Jianmin Wang, Philip L McCarthy, Elizabeth A Repasky, Hemn Mohammadpour.
      Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using β2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically.
    DOI:  https://doi.org/10.1038/s41467-024-47096-9
  6. Commun Biol. 2024 Mar 30. 7(1): 391
    Cytosolic retention of HtrA2 during mitochondrial protein import stress triggers the DELE1-HRI pathway.
    Paul Y Bi, Samuel A Killackey, Linus Schweizer, Damien Arnoult, Dana J Philpott, Stephen E Girardin.
      Mitochondrial stress inducers such as carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and oligomycin trigger the DELE1-HRI branch of the integrated stress response (ISR) pathway. Previous studies performed using epitope-tagged DELE1 showed that these stresses induced the cleavage of DELE1 to DELE1-S, which stimulates HRI. Here, we report that mitochondrial protein import stress (MPIS) is an overarching stress that triggers the DELE1-HRI pathway, and that endogenous DELE1 could be cleaved into two forms, DELE1-S and DELE1-VS, the latter accumulating only upon non-depolarizing MPIS. Surprisingly, while the mitochondrial protease OMA1 was crucial for DELE1 cleavage in HeLa cells, it was dispensable in HEK293T cells, suggesting that multiple proteases may be involved in DELE1 cleavage. In support, we identified a role for the mitochondrial protease, HtrA2, in mediating DELE1 cleavage into DELE1-VS, and showed that a Parkinson's disease (PD)-associated HtrA2 mutant displayed reduced DELE1 processing ability, suggesting a novel mechanism linking PD pathogenesis to mitochondrial stress. Our data further suggest that DELE1 is likely cleaved into DELE1-S in the cytosol, while the DELE1-VS form might be generated during halted translocation into mitochondria. Together, this study identifies MPIS as the overarching stress detected by DELE1 and identifies a novel role for HtrA2 in DELE1 processing.
    DOI:  https://doi.org/10.1038/s42003-024-06107-7
  7. Sci Adv. 2024 Apr 05. 10(14): eadl0389
    Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.
    Zhenqi Zhou, Alice Ma, Timothy M Moore, Dane M Wolf, Nicole Yang, Peter Tran, Mayuko Segawa, Alexander R Strumwasser, Wenjuan Ren, Kai Fu, Jonathan Wanagat, Alexander M van der Bliek, Rachelle Crosbie-Watson, Marc Liesa, Linsey Stiles, Rebecca Acin-Perez, Sushil Mahata, Orian Shirihai, Mark O Goodarzi, Michal Handzlik, Christian M Metallo, David W Walker, Andrea L Hevener.
      The dynamin-related guanosine triphosphatase, Drp1 (encoded by Dnm1l), plays a central role in mitochondrial fission and is requisite for numerous cellular processes; however, its role in muscle metabolism remains unclear. Here, we show that, among human tissues, the highest number of gene correlations with DNM1L is in skeletal muscle. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and impaired insulin action along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2 normalized complex II activity, lipid oxidation, and insulin action in Drp1-KD myocytes. Drp1 is critical in maintaining mitochondrial complex II assembly, lipid oxidation, and insulin sensitivity, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle metabolism, which is clinically relevant in combatting metabolic-related diseases.
    DOI:  https://doi.org/10.1126/sciadv.adl0389
  8. JCI Insight. 2024 Apr 02. pii: e169213. [Epub ahead of print]
    Role of the mitochondrial protein cyclophilin D in skin wound healing and collagen.
    Ritu Bansal, Monica Torres, Matthew Hunt, Nuoqi Wang, Margarita Chatzopoulou, Mansi Manchanda, Evan P Taddeo, Cynthia Shu, Orian S Shirihai, Etty Bachar-Wikstrom, Jakob D Wikstrom.
      Central for wound healing is the formation of granulation tissue, which largely consists of collagen and whose importance stretches past wound healing, including being implicated in both fibrosis and skin aging. Cyclophilin D (CyD) is a mitochondrial protein that regulates the permeability transition pore, known for its role in apoptosis and ischemia-reperfusion. To date, the role of CyD in human wound healing and collagen generation ihas been largely unexplored. Here, we show that CyD was upregulated in normal wounds and venous ulcers, likely adaptive as CyD inhibition impaired re-epithelialization, granulation tissue formation, and wound closure in both human and pig models. Overexpression of CyD increased keratinocyte migration and fibroblast proliferation, whilst its inhibition reduced migration. Independent of wound healing, CyD inhibition in fibroblasts reduced collagen secretion and caused endoplasmic reticulum collagen accumulation, while its overexpression increased collagen secretion. This was confirmed in a Ppif knockout mouse model, which showed a reduction in skin collagen. Overall, this study revealed previously unreported roles of CyD in skin, with implications for wound healing and beyond.
    Keywords:  Collagens; Dermatology; Mitochondria; Skin
    DOI:  https://doi.org/10.1172/jci.insight.169213
  9. Stem Cell Reports. 2024 Mar 26. pii: S2213-6711(24)00079-1. [Epub ahead of print]
    PINK1 deficiency alters muscle stem cell fate decision and muscle regenerative capacity.
    George Cairns, Madhavee Thumiah-Mootoo, Mah Rukh Abbasi, Melissa Gourlay, Jeremy Racine, Nikita Larionov, Alexandre Prola, Mireille Khacho, Yan Burelle.
      Maintenance of mitochondrial function plays a crucial role in the regulation of muscle stem cell (MuSC), but the underlying mechanisms remain ill defined. In this study, we monitored mitophagy in MuSCS under various myogenic states and examined the role of PINK1 in maintaining regenerative capacity. Results indicate that quiescent MuSCs actively express mitophagy genes and exhibit a measurable mitophagy flux and prominent mitochondrial localization to autophagolysosomes, which become rapidly decreased during activation. Genetic disruption of Pink1 in mice reduces PARKIN recruitment to mitochondria and mitophagy in quiescent MuSCs, which is accompanied by premature activation/commitment at the expense of self-renewal and progressive loss of muscle regeneration, but unhindered proliferation and differentiation capacity. Results also show that impaired fate decisions in PINK1-deficient MuSCs can be restored by scavenging excess mitochondrial ROS. These data shed light on the regulation of mitophagy in MuSCs and position PINK1 as an important regulator of their mitochondrial properties and fate decisions.
    Keywords:  fate decision; mitochondria; mitochondrial quality control; mitophagy; muscle regeneration; muscle stem cells
    DOI:  https://doi.org/10.1016/j.stemcr.2024.03.004
  10. Sci Rep. 2024 04 02. 14(1): 7739
    Identification and structural characterization of small molecule inhibitors of PINK1.
    Shafqat Rasool, Tara Shomali, Luc Truong, Nathalie Croteau, Simon Veyron, Bernardo A Bustillos, Wolfdieter Springer, Fabienne C Fiesel, Jean-François Trempe.
      Mutations in PINK1 and Parkin cause early-onset Parkinson's Disease (PD). PINK1 is a kinase which functions as a mitochondrial damage sensor and initiates mitochondrial quality control by accumulating on the damaged organelle. There, it phosphorylates ubiquitin, which in turn recruits and activates Parkin, an E3 ubiquitin ligase. Ubiquitylation of mitochondrial proteins leads to the autophagic degradation of the damaged organelle. Pharmacological modulation of PINK1 constitutes an appealing avenue to study its physiological function and develop therapeutics. In this study, we used a thermal shift assay with insect PINK1 to identify small molecules that inhibit ATP hydrolysis and ubiquitin phosphorylation. PRT062607, an SYK inhibitor, is the most potent inhibitor in our screen and inhibits both insect and human PINK1, with an IC50 in the 0.5-3 µM range in HeLa cells and dopaminergic neurons. The crystal structures of insect PINK1 bound to PRT062607 or CYC116 reveal how the compounds interact with the ATP-binding pocket. PRT062607 notably engages with the catalytic aspartate and causes a destabilization of insert-2 at the autophosphorylation dimer interface. While PRT062607 is not selective for PINK1, it provides a scaffold for the development of more selective and potent inhibitors of PINK1 that could be used as chemical probes.
    Keywords:  Inhibitor; Kinase; Mitochondria; PTEN‐induced kinase 1 (PINK1); Parkinson disease; Ubiquitin
    DOI:  https://doi.org/10.1038/s41598-024-58285-3
  11. Trends Biochem Sci. 2024 Apr 01. pii: S0968-0004(24)00071-9. [Epub ahead of print]
    Structural mechanisms of mitochondrial uncoupling protein 1 regulation in thermogenesis.
    Scott A Jones, Jonathan J Ruprecht, Paul G Crichton, Edmund R S Kunji.
      In mitochondria, the oxidation of nutrients is coupled to ATP synthesis by the generation of a protonmotive force across the mitochondrial inner membrane. In mammalian brown adipose tissue (BAT), uncoupling protein 1 (UCP1, SLC25A7), a member of the SLC25 mitochondrial carrier family, dissipates the protonmotive force by facilitating the return of protons to the mitochondrial matrix. This process short-circuits the mitochondrion, generating heat for non-shivering thermogenesis. Recent cryo-electron microscopy (cryo-EM) structures of human UCP1 have provided new molecular insights into the inhibition and activation of thermogenesis. Here, we discuss these structures, describing how purine nucleotides lock UCP1 in a proton-impermeable conformation and rationalizing potential conformational changes of this carrier in response to fatty acid activators that enable proton leak for thermogenesis.
    Keywords:  SLC25 mitochondrial carrier family; UCP1; bioenergetics; brown adipose tissue; non-shivering thermogenesis; thermogenin
    DOI:  https://doi.org/10.1016/j.tibs.2024.03.005
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