bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2025–01–26
fifteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. Mitochondrial protein import stress.
  2. TDP43 augments astrocyte inflammatory activity through mtDNA-cGAS-STING axis in NMOSD.
  3. Mitochondria complex III-generated superoxide is essential for IL-10 secretion in macrophages.
  4. Double-stranded RNA orbivirus disrupts the DNA-sensing cGAS-sting axis to prevent type I IFN induction.
  5. Immune evasion through mitochondrial transfer in the tumour microenvironment.
  6. Precise modelling of mitochondrial diseases using optimized mitoBEs.
  7. Optogenetic control of mitochondrial aggregation and function.
  8. Mitochondrial fatty acid oxidation regulates monocytic type I interferon signaling via histone acetylation.
  9. Urolithin A alleviates NLRP3 inflammasome activation and pyroptosis by promoting microglial mitophagy following spinal cord injury.
  10. Mitochondrial injury and complement dysregulation are drivers of pathological inflammation in viral myocarditis.
  11. Fis1 is required for the development of the dendritic mitochondrial network in pyramidal cortical neurons.
  12. Dengue virus and Zika virus alter endoplasmic reticulum-mitochondria contact sites to regulate respiration and apoptosis.
  13. Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.
  14. KNTC1 introduces segmental heterogeneity to mitochondria.
  15. Co-option of mitochondrial nucleic acid-sensing pathways by HSV-1 UL12.5 for reactivation from latent infection.
  1. Nat Cell Biol. 2025 Jan 22.
    Mitochondrial protein import stress.
    Nikolaus Pfanner, Fabian den Brave, Thomas Becker.
      Mitochondria have to import a large number of precursor proteins from the cytosol. Chaperones keep these proteins in a largely unfolded state and guide them to the mitochondrial import sites. Premature folding, mitochondrial stress and import defects can cause clogging of import sites and accumulation of non-imported precursors, representing a critical burden for cellular proteostasis. Here we discuss how cells respond to mitochondrial protein import stress by regenerating clogged import sites and inducing stress responses. The mitochondrial protein import machinery has a dual role by serving as sensor for detecting mitochondrial dysfunction and inducing stress-response pathways. The production of chaperones that fold or sequester precursor proteins in deposits is induced and the proteasomal activity is increased to remove the excess precursor proteins. Together, these pathways reveal how mitochondria are tightly integrated into a cellular proteostasis and stress response network to maintain cell viability.
    DOI:  https://doi.org/10.1038/s41556-024-01590-w
  2. J Neuroinflammation. 2025 Jan 22. 22(1): 14
    TDP43 augments astrocyte inflammatory activity through mtDNA-cGAS-STING axis in NMOSD.
    Zhuhe Liu, Yunmeng Bai, Bingtian Xu, Haixia Wen, Kechun Chen, Jingfang Lin, Yuanyuan Wang, Jiangping Xu, Haitao Wang, Fudong Shi, Jigang Wang, Honghao Wang.
      Abnormality in transactivating response region DNA binding protein 43 (TDP43) is well-recognized as the pathological hallmark of neurodegenerative diseases. However, the role of TDP43 in neuromyelitis optica spectrum disorder (NMOSD) remains unknown. Here, our observations demonstrate an upregulation of TDP43 in both in vitro and in vivo models of NMOSD, as well as in biological samples from NMOSD patients. Single-nucleus RNA sequencing revealed that NMOSD induced A1-like reactive astrocytes and astrocyte mitochondrial dysfunction in mice. We further found that NMOSD provoked the translocation of TDP43 to mitochondria and the release of mitochondrial DNA (mtDNA) into the cytoplasm. NMOSD caused activation of mtDNA/cyclic GMP-AMP synthase (cGAS) / stimulator of interferon genes (STING) pathway and A1-type inflammatory activation in astrocytes. Crucially, the knockdown of TDP43 markedly ameliorated NMOSD-induced mitochondrial dysfunction and the activation of the cGAS/STING pathway in astrocytes. Conversely, overexpression of TDP43 exacerbated these pathological changes. Specific silencing astrocytic TDP43 ameliorated NMOSD-induced injury in mice, and conversely, TDP43 overexpression intensified the injury. Meanwhile, both cGAS and STING inhibitors attenuated NMOSD-induced injury in mice. In summary, our data suggest that TDP43 exacerbates inflammatory activation of astrocytes in NMOSD through upregulating the mtDNA/cGAS/STING signaling pathway. Therefore, targeting TDP43 represents a compelling therapeutic strategy for NMOSD.
    Keywords:  Inflammatory activation; Mitochondrial dysfunction; NMOSD; TDP43; cGAS/STING
    DOI:  https://doi.org/10.1186/s12974-025-03348-z
  3. Sci Adv. 2025 Jan 24. 11(4): eadu4369
    Mitochondria complex III-generated superoxide is essential for IL-10 secretion in macrophages.
    Joshua S Stoolman, Rogan A Grant, Leah K Billingham, Taylor A Poor, Samuel E Weinberg, Madeline C Harding, Ziyan Lu, Jason Miska, Marten Szibor, Gr Scott Budinger, Navdeep S Chandel.
      Mitochondrial electron transport chain (ETC) function modulates macrophage biology; however, mechanisms underlying mitochondria ETC control of macrophage immune responses are not fully understood. Here, we report that mutant mice with mitochondria ETC complex III (CIII)-deficient macrophages exhibit increased susceptibility to influenza A virus (IAV) and LPS-induced endotoxic shock. Cultured bone marrow-derived macrophages (BMDMs) isolated from these mitochondria CIII-deficient mice released less IL-10 than controls following TLR3 or TLR4 stimulation. Unexpectedly, restoring mitochondrial respiration without generating superoxide using alternative oxidase (AOX) was not sufficient to reverse LPS-induced endotoxic shock susceptibility or restore IL-10 release. However, activation of protein kinase A (PKA) rescued IL-10 release in mitochondria CIII-deficient BMDMs following LPS stimulation. In addition, mitochondria CIII deficiency did not affect BMDM responses to interleukin-4 (IL-4) stimulation. Thus, our results highlight the essential role of mitochondria CIII-generated superoxide in the release of anti-inflammatory IL-10 in response to TLR stimulation.
    DOI:  https://doi.org/10.1126/sciadv.adu4369
  4. Cell Mol Life Sci. 2025 Jan 21. 82(1): 55
    Double-stranded RNA orbivirus disrupts the DNA-sensing cGAS-sting axis to prevent type I IFN induction.
    Andrés Louloudes-Lázaro, Pablo Nogales-Altozano, José M Rojas, Jeury Veloz, Ana B Carlón, Piet A Van Rijn, Verónica Martín, Ana Fernández-Sesma, Noemí Sevilla.
      Cyclic GMP-AMP synthase (cGAS) is a DNA sensing cellular receptor that induces IFN-I transcription in response to pathogen and host derived cytosolic DNA and can limit the replication of some RNA viruses. Some viruses have nonetheless evolved mechanisms to antagonize cGAS sensing. In this study, we evaluated the interaction between Bluetongue virus (BTV), the prototypical dsRNA virus of the Orbivirus genus and the Sedoreoviridae family, and cGAS. We found mitochondrial damage and DNA accumulation in the cytoplasm of infected cells. In addition, we show that BTV infection blocks DNA-induced IFN-I transcription and that virus infection prevents DNA sensing by inducing cGAS and STING degradation. We identify BTV-NS3 as the viral protein responsible for cGAS degradation, showing that NS3 physically interacts with cGAS and induces its degradation through an autophagy-dependent mechanism. Taken together, these findings identify for the first time a mechanism by which a dsRNA virus interferes with a DNA sensing pathway to evade the innate immune response.
    Keywords:  Autophagy; Bluetongue; Interferon; RNA virus; STING; cGAS
    DOI:  https://doi.org/10.1007/s00018-025-05580-5
  5. Nature. 2025 Jan 22.
    Immune evasion through mitochondrial transfer in the tumour microenvironment.
    Hideki Ikeda, Katsushige Kawase, Tatsuya Nishi, Tomofumi Watanabe, Keizo Takenaga, Takashi Inozume, Takamasa Ishino, Sho Aki, Jason Lin, Shusuke Kawashima, Joji Nagasaki, Youki Ueda, Shinichiro Suzuki, Hideki Makinoshima, Makiko Itami, Yuki Nakamura, Yasutoshi Tatsumi, Yusuke Suenaga, Takao Morinaga, Akiko Honobe-Tabuchi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yasuhiro Nakamura, Yukiko Kiniwa, Eiki Ichihara, Hidetoshi Hayashi, Jun-Ichiro Ikeda, Toyoyuki Hanazawa, Shinichi Toyooka, Hiroyuki Mano, Takuji Suzuki, Tsuyoshi Osawa, Masahito Kawazu, Yosuke Togashi.
      Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack1. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses2-4. However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs. Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo. Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies.
    DOI:  https://doi.org/10.1038/s41586-024-08439-0
  6. Nature. 2025 Jan 22.
    Precise modelling of mitochondrial diseases using optimized mitoBEs.
    Xiaoxue Zhang, Xue Zhang, Jiwu Ren, Jiayi Li, Xiaoxu Wei, Ying Yu, Zongyi Yi, Wensheng Wei.
      The development of animal models is crucial for studying and treating mitochondrial diseases. Here we optimized adenine and cytosine deaminases to reduce off-target effects on the transcriptome and the mitochondrial genome, improving the accuracy and efficiency of our newly developed mitochondrial base editors (mitoBEs)1. Using these upgraded mitoBEs (version 2 (v2)), we targeted 70 mouse mitochondrial DNA mutations analogous to human pathogenic variants2, establishing a foundation for mitochondrial disease mouse models. Circular RNA-encoded mitoBEs v2 achieved up to 82% editing efficiency in mice without detectable off-target effects in the nuclear genome. The edited mitochondrial DNA persisted across various tissues and was maternally inherited, resulting in F1 generation mice with mutation loads as high as 100% and some mice exhibiting editing only at the target site. By optimizing the transcription activator-like effector (TALE) binding site, we developed a single-base-editing mouse model for the mt-Nd5 A12784G mutation. Phenotypic evaluations led to the creation of mouse models for the mt-Atp6 T8591C and mt-Nd5 A12784G mutations, exhibiting phenotypes corresponding to the reduced heart rate seen in Leigh syndrome and the vision loss characteristic of Leber's hereditary optic neuropathy, respectively. Moreover, the mt-Atp6 T8591C mutation proved to be more deleterious than mt-Nd5 A12784G, affecting embryonic development and rapidly diminishing through successive generations. These upgraded mitoBEs offer a highly efficient and precise strategy for constructing mitochondrial disease models, laying a foundation for further research in this field.
    DOI:  https://doi.org/10.1038/s41586-024-08469-8
  7. Front Bioeng Biotechnol. 2024 ;12 1500343
    Optogenetic control of mitochondrial aggregation and function.
    Luhao Zhang, Xuechun Liu, Min Zhu, Yuanfa Yao, Zhichao Liu, Xianming Zhang, Xin Deng, Yi Wang, Liting Duan, Xiaogang Guo, Junfen Fu, Yingke Xu.
      The balance of mitochondrial fission and fusion plays an important role in maintaining the stability of cellular homeostasis. Abnormal mitochondrial fission and fragmentation have been shown to be associated with oxidative stress, which causes a variety of human diseases from neurodegeneration disease to cancer. Therefore, the induction of mitochondrial aggregation and fusion may provide an alternative approach to alleviate these conditions. Here, an optogenetic-based mitochondrial aggregation system (Opto-MitoA) developed, which is based on the CRY2clust/CIBN light-sensitive module. Upon blue light illumination, CRY2clust relocates from the cytosol to mitochondria where it induces mitochondrial aggregation by CRY2clust homo-oligomerization and CRY2clust-CIBN hetero-dimerization. Our functional experiments demonstrate that Opto-MitoA-induced mitochondrial aggregation potently alleviates niclosamide-caused cell dysfunction in ATP production. This study establishes a novel optogenetic-based strategy to regulate mitochondrial dynamics in cells, which may provide a potential therapy for treating mitochondrial-related diseases.
    Keywords:  ATP; aggregation; imaging; mitochondria; optogenetics
    DOI:  https://doi.org/10.3389/fbioe.2024.1500343
  8. Sci Adv. 2025 Jan 24. 11(4): eadq9301
    Mitochondrial fatty acid oxidation regulates monocytic type I interferon signaling via histone acetylation.
    Jing Wu, Komudi Singh, Vivian Shing, Anand Gupta, Brett C Arenberg, Rebecca D Huffstutler, Duck-Yeon Lee, Michael N Sack.
      Although lipid-derived acetyl-coenzyme A (CoA) is a major carbon source for histone acetylation, the contribution of fatty acid β-oxidation (FAO) to this process remains poorly characterized. To investigate this, we generated mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1, distal FAO enzyme) knockout macrophages. 13C-carbon tracing confirmed reduced FA-derived carbon incorporation into histone H3, and RNA sequencing identified diminished interferon-stimulated gene expression in the absence of ACAT1. Chromatin accessibility at the Stat1 locus was diminished in ACAT1-/- cells. Chromatin immunoprecipitation analysis demonstrated reduced acetyl-H3 binding to Stat1 promoter/enhancer regions, and increasing histone acetylation rescued Stat1 expression. Interferon-β release was blunted in ACAT1-/- and recovered by ACAT1 reconstitution. Furthermore, ACAT1-dependent histone acetylation required an intact acetylcarnitine shuttle. Last, obese subjects' monocytes exhibited increased ACAT1 and histone acetylation levels. Thus, our study identifies an intriguing link between FAO-mediated epigenetic control of type I interferon signaling and uncovers a potential mechanistic nexus between obesity and type I interferon signaling.
    DOI:  https://doi.org/10.1126/sciadv.adq9301
  9. Int Immunopharmacol. 2025 Jan 18. pii: S1567-5769(25)00046-3. [Epub ahead of print]148 114057
    Urolithin A alleviates NLRP3 inflammasome activation and pyroptosis by promoting microglial mitophagy following spinal cord injury.
    Kongbin Chen, Jiahao Ying, Jiangwei Zhu, Liang Chen, Rongjie Liu, Mengqi Jing, Yuchao Wang, Kailiang Zhou, Long Wu, Chenyu Wu, Jian Xiao, Wenfei Ni.
      Spinal cord injury (SCI) is a potentially fatal condition that often results in loss of motor and sensory functions, thereby significantly burdening global health initiatives. Urolithin A (UA), an intestinal microbial metabolite of ellagic acid, is known for its potent anti-inflammatory properties in chronic inflammation contexts. UA treatment in humans induces a molecular signature of improved mitochondrial and cellular health. Yet, its effects on acute inflammation following SCI remain unclear. In this study, we developed an impact-induced mouse model for SCI and treated the injured mice with UA (50 mg/kg/d, till 8 weeks) via intragastric administration. Furthermore, we subjected BV2 cells to lipopolysaccharide and adenosine 5'-triphosphate to simulate the post-injury inflammatory response. Our results demonstrated that pre-treatment with UA (10 μM) effectively inhibited NLRP3 inflammasome activation in LPS-primed BV2 cells. This inhibition was evidenced by reduced cleaved Caspase-1 and mature IL-1β release, diminished ASC speck formation, and decreased gasdermin D (GSDMD)-mediated pyroptosis. Additionally, UA treatment restored mitochondrial activity and ROS production attenuated by NLRP3 activation, increased LC3-II expression, and enhanced LC3 co-localization with mitochondria. 3-Methyladenine (3-MA), an autophagy inhibitor, can partially reverse the stimulatory effect of UA on mitophagy, as well as the inhibitory effect of UA on pyroptosis. This study highlighted the protective role of UA against SCI through its promotion of mitophagy, which in turn inhibits NLRP3 inflammasome activation and pyroptosis.
    Keywords:  Autophagy; Mitophagy; NLRP3 inflammasome; Pyroptosis; Spinal cord injury; Urolithin A
    DOI:  https://doi.org/10.1016/j.intimp.2025.114057
  10. J Virol. 2025 Jan 23. e0180424
    Mitochondrial injury and complement dysregulation are drivers of pathological inflammation in viral myocarditis.
    Yasir Mohamud, Amirhossein Bahreyni, Sinwoo Wendy Hwang, Jingfei Carly Lin, Zhihan Claire Wang, Jingchun Zhang, Honglin Luo.
      Enteroviruses cause nearly 1 billion global infections annually and are associated with a diverse array of human illnesses. Among these, myocarditis and the resulting chronic inflammation have been recognized as major contributing factors to virus-induced heart failure. Despite our growing understanding, very limited therapeutic strategies have been developed to address the pathological consequences of virus-induced chronic innate immune activation. Coxsackievirus B3 (CVB3) was used as a model cardiotropic enterovirus. We leveraged in vitro cell-based studies to investigate cardiomyocyte and macrophage interaction during CVB3 infection, as well as animal studies and unique human cardio specimens to evaluate mechanisms of viral heart injury. We present evidence that viral myocarditis is in part exacerbated by pathological activation of the complement pathway in cells, mice, and human cardiac tissues. We demonstrate unique cell type-specific responses to viral infection that are exacerbated by mitochondrial injury in cardiomyocytes and NFκB-dependent pro-inflammatory response in macrophages. Macrophages are robustly activated by damage-associated mitochondrial components, including mitochondrial proteins and lipid extracts. Mechanistically, we identify complement protective factors CD59/protectin and CD55/DAF as novel targets of viral proteinase that acts to release the brakes on complement-mediated autoinjury. Collectively, our study highlights a novel mechanism that can act as a potential contributor to CVB3 pathogenesis through mitochondrial injury-mediated autoimmunity.
    IMPORTANCE: This study sheds light on how enteroviruses, specifically coxsackievirus B3, may contribute to heart failure by triggering harmful immune responses in the heart. We discovered that viral infections in heart cells cause mitochondrial damage, which in turn activates a destructive immune response involving the complement system. This immune activation is one of the significant contributors that lead to further injury of heart tissues, worsening the damage caused by the virus. Additionally, we identified key protective molecules that are targeted and disrupted by the virus, allowing the immune system to attack the heart even more aggressively. Understanding these mechanisms may provide additional insights into how viral infections can lead to chronic heart conditions and suggests potential therapeutic targets to prevent or reduce heart damage in patients affected by viral myocarditis.
    Keywords:  cd55; cd59; complement; coxsackievirus b3; heart failure; inflammation; mitochondria; myocarditis
    DOI:  https://doi.org/10.1128/jvi.01804-24
  11. bioRxiv. 2025 Jan 07. pii: 2025.01.07.631801. [Epub ahead of print]
    Fis1 is required for the development of the dendritic mitochondrial network in pyramidal cortical neurons.
    Klaudia Strucinska, Parker Kneis, Travis Pennington, Katarzyna Cizio, Patrycja Szybowska, Abigail Morgan, Joshua Weertman, Tommy L Lewis.
      Mitochondrial ATP production and calcium buffering are critical for metabolic regulation and neurotransmission making the formation and maintenance of the mitochondrial network a critical component of neuronal health. Cortical pyramidal neurons contain compartment-specific mitochondrial morphologies that result from distinct axonal and dendritic mitochondrial fission and fusion profiles. We previously showed that axonal mitochondria are maintained at a small size as a result of high axonal mitochondrial fission factor (Mff) activity. However, loss of Mff activity had little effect on cortical dendritic mitochondria, raising the question of how fission/fusion balance is controlled in the dendrites. Thus, we sought to investigate the role of another fission factor, fission 1 (Fis1), on mitochondrial morphology, dynamics and function in cortical neurons. We knocked down Fis1 in cortical neurons both in primary culture and in vivo , and unexpectedly found that Fis1 depletion decreased mitochondrial length in the dendrites, without affecting mitochondrial size in the axon. Further, loss of Fis1 activity resulted in both increased mitochondrial motility and dynamics in the dendrites. These results argue Fis1 exhibits dendrite selectivity and plays a more complex role in neuronal mitochondrial dynamics than previously reported. Functionally, Fis1 loss resulted in reduced mitochondrial membrane potential, increased sensitivity to complex III blockade, and decreased mitochondrial calcium uptake during neuronal activity. The altered mitochondrial network culminated in elevated resting calcium levels that increased dendritic branching but reduced spine density. We conclude that Fis1 regulates morphological and functional mitochondrial characteristics that influence dendritic tree arborization and connectivity.
    DOI:  https://doi.org/10.1101/2025.01.07.631801
  12. iScience. 2025 Jan 17. 28(1): 111599
    Dengue virus and Zika virus alter endoplasmic reticulum-mitochondria contact sites to regulate respiration and apoptosis.
    Wesley Freppel, Viviana Andrea Barragan Torres, Olus Uyar, Anaïs Anton, Zaynab Nouhi, Mathilde Broquière, Clément Mazeaud, Aïssatou Aïcha Sow, Alexanne Léveillé, Claudia Gilbert, Nicolas Tremblay, Jonathan Eintrez Owen, Cheyanne L Bemis, Xavier Laulhé, Alain Lamarre, Christopher J Neufeldt, Ian Gaël Rodrigue-Gervais, Andreas Pichlmair, Denis Girard, Pietro Scaturro, Laura Hulea, Laurent Chatel-Chaix.
      During infection, dengue virus (DENV) and Zika virus (ZIKV), two (ortho)flaviviruses of public health concern worldwide, induce alterations of mitochondria morphology to favor viral replication, suggesting a viral co-opting of mitochondria functions. Here, we performed an extensive transmission electron microscopy-based quantitative analysis to demonstrate that both DENV and ZIKV alter endoplasmic reticulum-mitochondria contact sites (ERMC). This correlated at the molecular level with an impairment of ERMC tethering protein complexes located at the surface of both organelles. Furthermore, virus infection modulated the mitochondrial oxygen consumption rate. Consistently, metabolomic and mitoproteomic analyses revealed a decrease in the abundance of several metabolites of the Krebs cycle and changes in the stoichiometry of the electron transport chain. Most importantly, ERMC destabilization by protein knockdown increased virus replication while dampening ZIKV-induced apoptosis. Overall, our results support the notion that flaviviruses hijack ERMCs to generate a cytoplasmic environment beneficial for sustained and efficient replication.
    Keywords:  Cell biology; Membranes; Metabolomics; Proteomics; Virology
    DOI:  https://doi.org/10.1016/j.isci.2024.111599
  13. Nat Cancer. 2025 Jan 17.
    Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.
    Jiaxin Liang, Tevis Vitale, Xixi Zhang, Thomas D Jackson, Deyang Yu, Mark Jedrychowski, Steve P Gygi, Hans R Widlund, Kai W Wucherpfennig, Pere Puigserver.
      Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.
    DOI:  https://doi.org/10.1038/s43018-024-00895-x
  14. Dis Model Mech. 2025 Jan 20. pii: dmm.052063. [Epub ahead of print]
    KNTC1 introduces segmental heterogeneity to mitochondria.
    Atsushi Tsukamura, Hirotaka Ariyama, Natsuki Hayashi, Satoko Miyatake, Satoko Okado, Sara Sultana, Ichiro Terakado, Takefumi Yamamoto, Shoji Yamanaka, Satoshi Fujii, Haruka Hamanoue, Ryoko Asano, Taichi Mizushima, Naomichi Matsumoto, Yoshihiro Maruo, Masaki Mori.
      Mitochondria contribute to cellular metabolism by providing a specialised milieu for energising cells by incorporating and processing the metabolites. However, heterogeneity in the mitochondria within is only partially elucidated. Mitochondria dynamically alter their morphology and functions during the life of animals, in which cells proliferate and grow. We here show that Kntc1, a highly evolutionarily conserved protein, translocates from the Golgi apparatus to linear mitochondrial segments (LMS) upon glutamine deprivation and plays an essential role in maintaining LMS. The LMS with Kntc1 localisation exhibits an increase in the membrane potential, suggesting the role of Kntc1 in functioning as a reservoir for the energy-generating potential. Suppression of Kntc1 leads to glutamine consumption and lactate production, thus impacting cellular metabolism, eventually leading to anchorage-independent growth of cells. Indeed, the KNTC1 variant was identified in a patient with ovarian cancer, suggesting that segmental regulation of the mitochondrial function is essential for maintaining tissue integrity.
    Keywords:  Bent mitochondrial segment (BMS); Glutamine metabolism; KNTC1; Linear mitochondrial segment (LMS); Mitochondrial structural heterogeneity
    DOI:  https://doi.org/10.1242/dmm.052063
  15. Proc Natl Acad Sci U S A. 2025 Jan 28. 122(4): e2413965122
    Co-option of mitochondrial nucleic acid-sensing pathways by HSV-1 UL12.5 for reactivation from latent infection.
    Patryk A Krakowiak, Matthew E Flores, Sean R Cuddy, Abigail L Whitford, Sara A Dochnal, Aleksandra Babnis, Tsuyoshi Miyake, Marco Tigano, Daniel A Engel, Anna R Cliffe.
      Although viruses subvert innate immune pathways for their replication, there is evidence they can also co-opt antiviral responses for their benefit. The ubiquitous human pathogen, Herpes simplex virus-1 (HSV-1), encodes a protein (UL12.5) that induces the release of mitochondrial nucleic acid into the cytosol, which activates immune-sensing pathways and reduces productive replication in nonneuronal cells. HSV-1 establishes latency in neurons and can reactivate to cause disease. We found that UL12.5 is required for HSV-1 reactivation in neurons and acts to directly promote viral lytic gene expression during initial exit from latency. Further, the direct activation of innate immune-sensing pathways triggered HSV-1 reactivation and compensated for a lack of UL12.5. Finally, we found that the induction of HSV-1 lytic genes during reactivation required intact RNA- and DNA-sensing pathways, demonstrating that HSV-1 can respond to and active antiviral nucleic acid-sensing pathways to reactivate from a latent infection.
    Keywords:  STING; UL12.5; herpes simplex virus; mitochondrial DNA; reactivation
    DOI:  https://doi.org/10.1073/pnas.2413965122
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