bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2024‒02‒04
twelve papers selected by
Marco Tigano, Thomas Jefferson University
  1. Stress response silencing by an E3 ligase mutated in neurodegeneration.
  2. Linear DNA-driven recombination in mammalian mitochondria.
  3. Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.
  4. Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.
  5. Recapitulating and reversing human brain ribosomopathy defects via the maladaptive integrated stress response.
  6. Beneficial Effects of Low-Grade Mitochondrial Stress on Metabolic Diseases and Aging.
  7. XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells.
  8. Multiple mechanisms activate GCN2 eIF2 kinase in response to diverse stress conditions.
  9. ARK5 enhances cell survival associated with mitochondrial morphological dynamics from fusion to fission in human multiple myeloma cells.
  10. OPA1 mutation affects autophagy and triggers senescence in autosomal dominant optic atrophy plus fibroblasts.
  11. Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity.
  12. Mitochondrial HER2 stimulates respiration and promotes tumorigenicity.
  1. Nature. 2024 Jan 31.
    Stress response silencing by an E3 ligase mutated in neurodegeneration.
    Diane L Haakonsen, Michael Heider, Andrew J Ingersoll, Kayla Vodehnal, Samuel R Witus, Takeshi Uenaka, Marius Wernig, Michael Rapé.
      Stress response pathways detect and alleviate adverse conditions to safeguard cell and tissue homeostasis, yet their prolonged activation induces apoptosis and disrupts organismal health1-3. How stress responses are turned off at the right time and place remains poorly understood. Here we report a ubiquitin-dependent mechanism that silences the cellular response to mitochondrial protein import stress. Crucial to this process is the silencing factor of the integrated stress response (SIFI), a large E3 ligase complex mutated in ataxia and in early-onset dementia that degrades both unimported mitochondrial precursors and stress response components. By recognizing bifunctional substrate motifs that equally encode protein localization and stability, the SIFI complex turns off a general stress response after a specific stress event has been resolved. Pharmacological stress response silencing sustains cell survival even if stress resolution failed, which underscores the importance of signal termination and provides a roadmap for treating neurodegenerative diseases caused by mitochondrial import defects.
    DOI:  https://doi.org/10.1038/s41586-023-06985-7
  2. Nucleic Acids Res. 2024 Feb 01. pii: gkae040. [Epub ahead of print]
    Linear DNA-driven recombination in mammalian mitochondria.
    Georgios Fragkoulis, Anu Hangas, Zsófia Fekete, Craig Michell, Carlos T Moraes, Smaranda Willcox, Jack D Griffith, Steffi Goffart, Jaakko L O Pohjoismäki.
      Mitochondrial DNA (mtDNA) recombination in animals has remained enigmatic due to its uniparental inheritance and subsequent homoplasmic state, which excludes the biological need for genetic recombination, as well as limits tools to study it. However, molecular recombination is an important genome maintenance mechanism for all organisms, most notably being required for double-strand break repair. To demonstrate the existence of mtDNA recombination, we took advantage of a cell model with two different types of mitochondrial genomes and impaired its ability to degrade broken mtDNA. The resulting excess of linear DNA fragments caused increased formation of cruciform mtDNA, appearance of heterodimeric mtDNA complexes and recombinant mtDNA genomes, detectable by Southern blot and by long range PacBio® HiFi sequencing approach. Besides utilizing different electrophoretic methods, we also directly observed molecular complexes between different mtDNA haplotypes and recombination intermediates using transmission electron microscopy. We propose that the known copy-choice recombination by mitochondrial replisome could be sufficient for the needs of the small genome, thus removing the requirement for a specialized mitochondrial recombinase. The error-proneness of this system is likely to contribute to the formation of pathological mtDNA rearrangements.
    DOI:  https://doi.org/10.1093/nar/gkae040
  3. Nat Commun. 2024 Jan 27. 15(1): 830
    Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.
    Juan Ignacio Jiménez-Loygorri, Beatriz Villarejo-Zori, Álvaro Viedma-Poyatos, Juan Zapata-Muñoz, Rocío Benítez-Fernández, María Dolores Frutos-Lisón, Francisco A Tomás-Barberán, Juan Carlos Espín, Estela Area-Gómez, Aurora Gomez-Duran, Patricia Boya.
      Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy is either increased or unchanged in old versus young mice. Transcriptomic analysis shows marked upregulation of the type I interferon response in the retina of old mice, which correlates with increased levels of cytosolic mtDNA and activation of the cGAS/STING pathway. Crucially, these same alterations are replicated in primary human fibroblasts from elderly donors. In old mice, pharmacological induction of mitophagy with urolithin A attenuates cGAS/STING activation and ameliorates deterioration of neurological function. These findings point to mitophagy induction as a strategy to decrease age-associated inflammation and increase healthspan.
    DOI:  https://doi.org/10.1038/s41467-024-45044-1
  4. Nat Cancer. 2024 Jan 29.
    Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.
    Mahnoor Mahmood, Eric Minwei Liu, Amy L Shergold, Elisabetta Tolla, Jacqueline Tait-Mulder, Alejandro Huerta-Uribe, Engy Shokry, Alex L Young, Sergio Lilla, Minsoo Kim, Tricia Park, Sonia Boscenco, Javier L Manchon, Crístina Rodríguez-Antona, Rowan C Walters, Roger J Springett, James N Blaza, Louise Mitchell, Karen Blyth, Sara Zanivan, David Sumpton, Edward W Roberts, Ed Reznik, Payam A Gammage.
      The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.
    DOI:  https://doi.org/10.1038/s43018-023-00721-w
  5. Sci Adv. 2024 Feb 02. 10(5): eadk1034
    Recapitulating and reversing human brain ribosomopathy defects via the maladaptive integrated stress response.
    Wei Zhang, Minjie Zhang, Li Ma, Supawadee Jariyasakulroj, Qing Chang, Ziying Lin, Zhipeng Lu, Jian-Fu Chen.
      Animal or human models recapitulating brain ribosomopathies are incomplete, hampering development of urgently needed therapies. Here, we generated genetic mouse and human cerebral organoid models of brain ribosomopathies, caused by mutations in small nucleolar RNA (snoRNA) SNORD118. Both models exhibited protein synthesis loss, proteotoxic stress, and p53 activation and led to decreased proliferation and increased death of neural progenitor cells (NPCs), resulting in brain growth retardation, recapitulating features in human patients. Loss of SNORD118 function resulted in an aberrant upregulation of p-eIF2α, the mediator of integrated stress response (ISR). Using human iPSC cell-based screen, we identified small-molecule 2BAct, an ISR inhibitor, which potently reverses mutant NPC defects. Targeting ISR by 2BAct mitigated ribosomopathy defects in both cerebral organoid and mouse models. Thus, our SNORD118 mutant organoid and mice recapitulate human brain ribosomopathies and cross-validate maladaptive ISR as a key disease-driving mechanism, pointing to a therapeutic intervention strategy.
    DOI:  https://doi.org/10.1126/sciadv.adk1034
  6. Yonsei Med J. 2024 Feb;65(2): 55-69
    Beneficial Effects of Low-Grade Mitochondrial Stress on Metabolic Diseases and Aging.
    Se Hee Min, Gil Myoung Kang, Jae Woo Park, Min-Seon Kim.
      Mitochondria function as platforms for bioenergetics, nutrient metabolism, intracellular signaling, innate immunity regulators, and modulators of stem cell activity. Thus, the decline in mitochondrial functions causes or correlates with diabetes mellitus and many aging-related diseases. Upon stress or damage, the mitochondria elicit a series of adaptive responses to overcome stress and restore their structural integrity and functional homeostasis. These adaptive responses to low-level or transient mitochondrial stress promote health and resilience to upcoming stress. Beneficial effects of low-grade mitochondrial stress, termed mitohormesis, have been observed in various organisms, including mammals. Accumulated evidence indicates that treatments boosting mitohormesis have therapeutic potential in various human diseases accompanied by mitochondrial stress. Here, we review multiple cellular signaling pathways and interorgan communication mechanisms through which mitochondrial stress leads to advantageous outcomes. We also discuss the relevance of mitohormesis in obesity, diabetes, metabolic liver disease, aging, and exercise.
    Keywords:  Mitochondria; aging; diabetes; hormesis; obesity; stress
    DOI:  https://doi.org/10.3349/ymj.2023.0131
  7. Cell Rep. 2024 Feb 01. pii: S2211-1247(24)00111-6. [Epub ahead of print]43(2): 113783
    XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells.
    Tao Zou, Meng Zhou, Akansha Gupta, Patrick Zhuang, Alyssa R Fishbein, Hope Y Wei, Diego Capcha-Rodriguez, Zhouwei Zhang, Andrew D Cherniack, Matthew Meyerson.
      
    DOI:  https://doi.org/10.1016/j.celrep.2024.113783
  8. Nucleic Acids Res. 2024 Jan 28. pii: gkae006. [Epub ahead of print]
    Multiple mechanisms activate GCN2 eIF2 kinase in response to diverse stress conditions.
    Jagannath Misra, Kenneth R Carlson, Dan F Spandau, Ronald C Wek.
      Diverse environmental insults induce the integrated stress response (ISR), which features eIF2 phosphorylation and translational control that serves to restore protein homeostasis. The eIF2 kinase GCN2 is a first responder in the ISR that is activated by amino acid depletion and other stresses not directly related to nutrients. Two mechanisms are suggested to trigger an ordered process of GCN2 activation during stress: GCN2 monitoring stress via accumulating uncharged tRNAs or by stalled and colliding ribosomes. Our results suggest that while ribosomal collisions are indeed essential for GCN2 activation in response to translational elongation inhibitors, conditions that trigger deacylation of tRNAs activate GCN2 via its direct association with affected tRNAs. Both mechanisms require the GCN2 regulatory domain related to histidyl tRNA synthetases. GCN2 activation by UV irradiation features lowered amino acids and increased uncharged tRNAs and UV-induced ribosome collisions are suggested to be dispensable. We conclude that there are multiple mechanisms that activate GCN2 during diverse stresses.
    DOI:  https://doi.org/10.1093/nar/gkae006
  9. Cell Death Discov. 2024 Jan 29. 10(1): 56
    ARK5 enhances cell survival associated with mitochondrial morphological dynamics from fusion to fission in human multiple myeloma cells.
    Sivasundaram Karnan, Ichiro Hanamura, Akinobu Ota, Lam Quang Vu, Kaori Uchino, Tomohiro Horio, Satsuki Murakami, Shohei Mizuno, Md Lutfur Rahman, Md Wahiduzzaman, Muhammad Nazmul Hasan, Mrityunjoy Biswas, Toshinori Hyodo, Hideaki Ito, Atsushi Suzuki, Hiroyuki Konishi, Shinobu Tsuzuki, Yoshitaka Hosokawa, Akiyoshi Takami.
      5' adenosine monophosphate-activated protein kinase-related kinase 5 (ARK5) is involved in mitochondrial ATP production and associated with poor prognosis of multiple myeloma (MM). However, the molecular mechanisms of ARK5 in MM remain largely unknown. This study examined the pathogenic role of ARK5 in mitochondria by using genetically modified isogenic cell clones with or without ARK5 in human myeloma cell lines, KMS-11 and Sachi, which overexpress ARK5. The biallelic knockout of ARK5 (ARK5-KO) inhibited cell proliferation, colony formation, and migration with increased apoptosis. Mitochondrial fusion was enhanced in ARK5-KO cells, unlike in ARK5 wild-type (ARK5-WT) cells, which exhibited increased mitochondrial fission. Furthermore, ARK5-KO cells demonstrated a lower phosphorylated dynamin-related protein 1 at serine 616, higher protein expression of mitofusin-1 (MFN1) and MFN2, optic atrophy 1 with a lower level of ATP, and higher levels of lactate and reactive oxygen species than ARK5-WT cells. Our findings suggest that ARK5-enhanced myeloma cells can survive associated mitochondrial fission and activity. This study first revealed the relationship between ARK5 and mitochondrial morphological dynamics. Thus, our outcomes show novel aspects of mitochondrial biology of ARK5, which can afford a more advanced treatment approach for unfavorable MM expressing ARK5.
    DOI:  https://doi.org/10.1038/s41420-024-01814-w
  10. Hum Mol Genet. 2024 Jan 27. pii: ddae008. [Epub ahead of print]
    OPA1 mutation affects autophagy and triggers senescence in autosomal dominant optic atrophy plus fibroblasts.
    Paola Zanfardino, Alessandro Amati, Stefano Doccini, Sharon N Cox, Apollonia Tullo, Giovanna Longo, Annamaria D'Erchia, Ernesto Picardi, Claudia Nesti, Filippo M Santorelli, Vittoria Petruzzella.
      In several cases of mitochondrial diseases, the underlying genetic and bioenergetic causes of reduced oxidative phosphorylation (OxPhos) in mitochondrial dysfunction are well understood. However, there is still limited knowledge about the specific cellular outcomes and factors involved for each gene and mutation, which contributes to the lack of effective treatments for these disorders. This study focused on fibroblasts from a patient with Autosomal Dominant Optic Atrophy (ADOA) plus syndrome harboring a mutation in the Optic Atrophy 1 (OPA1) gene. By combining functional and transcriptomic approaches, we investigated the mitochondrial function and identified cellular phenotypes associated with the disease. Our findings revealed that fibroblasts with the OPA1 mutation exhibited a disrupted mitochondrial network and function, leading to altered mitochondrial dynamics and reduced autophagic response. Additionally, we observed a premature senescence phenotype in these cells, suggesting a previously unexplored role of the OPA1 gene in inducing senescence in ADOA plus patients. This study provides novel insights into the mechanisms underlying mitochondrial dysfunction in ADOA plus and highlights the potential importance of senescence in disease progression.
    Keywords:  ADOA plus; Autophagy; OPA1; mitochondria; mitophagy; senescence
    DOI:  https://doi.org/10.1093/hmg/ddae008
  11. Nat Commun. 2024 Feb 01. 15(1): 953
    Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity.
    Yuki Takakura, Moeka Machida, Natsumi Terada, Yuka Katsumi, Seika Kawamura, Kenta Horie, Maki Miyauchi, Tatsuya Ishikawa, Nobuko Akiyama, Takao Seki, Takahisa Miyao, Mio Hayama, Rin Endo, Hiroto Ishii, Yuya Maruyama, Naho Hagiwara, Tetsuya J Kobayashi, Naoto Yamaguchi, Hiroyuki Takano, Taishin Akiyama, Noritaka Yamaguchi.
      Autophagy is primarily activated by cellular stress, such as starvation or mitochondrial damage. However, stress-independent autophagy is activated by unclear mechanisms in several cell types, such as thymic epithelial cells (TECs). Here we report that the mitochondrial protein, C15ORF48, is a critical inducer of stress-independent autophagy. Mechanistically, C15ORF48 reduces the mitochondrial membrane potential and lowers intracellular ATP levels, thereby activating AMP-activated protein kinase and its downstream Unc-51-like kinase 1. Interestingly, C15ORF48-dependent induction of autophagy upregulates intracellular glutathione levels, promoting cell survival by reducing oxidative stress. Mice deficient in C15orf48 show a reduction in stress-independent autophagy in TECs, but not in typical starvation-induced autophagy in skeletal muscles. Moreover, C15orf48-/- mice develop autoimmunity, which is consistent with the fact that the stress-independent autophagy in TECs is crucial for the thymic self-tolerance. These results suggest that C15ORF48 induces stress-independent autophagy, thereby regulating oxidative stress and self-tolerance.
    DOI:  https://doi.org/10.1038/s41467-024-45206-1
  12. Eur J Clin Invest. 2024 Jan 30. e14174
    Mitochondrial HER2 stimulates respiration and promotes tumorigenicity.
    Eliska Novotna, Mirko Milosevic, Dana Prukova, Silvia Magalhaes-Novais, Sarka Dvorakova, Kristina Dmytruk, Jakub Gemperle, Dagmar Zudova, Tereza Nickl, Marek Vrbacky, Daniel Rosel, Vlada Filimonenko, Jan Prochazka, Jan Brabek, Jiri Neuzil, Katerina Rohlenova, Jakub Rohlena.
      BACKGROUND: Amplification of HER2, a receptor tyrosine kinase and a breast cancer-linked oncogene, is associated with aggressive disease. HER2 protein is localised mostly at the cell membrane, but a fraction translocates to mitochondria. Whether and how mitochondrial HER2 contributes to tumorigenicity is currently unknown.METHODS: We enriched the mitochondrial (mt-)HER2 fraction in breast cancer cells using an N-terminal mitochondrial targeting sequence and analysed how this manipulation impacts bioenergetics and tumorigenic properties. The role of the tyrosine kinase activity of mt-HER2 was assessed in wild type, kinase-dead (K753M) and kinase-enhanced (V659E) mtHER2 constructs.
    RESULTS: We document that mt-HER2 associates with the oxidative phosphorylation system, stimulates bioenergetics and promotes larger respiratory supercomplexes. mt-HER2 enhances proliferation and invasiveness in vitro and tumour growth and metastatic potential in vivo, in a kinase activity-dependent manner. On the other hand, constitutively active mt-HER2 provokes excessive mitochondria ROS generation, sensitises to cell death, and restricts growth of primary tumours, suggesting that regulation of HER2 activity in mitochondria is required for the maximal pro-tumorigenic effect.
    CONCLUSIONS: mt-HER2 promotes tumorigenicity by supporting bioenergetics and optimal redox balance.
    Keywords:  HER2; cancer; electron transport chain; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1111/eci.14174
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