bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2024–08–25
sixteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. Structural basis for substrate binding and selection by human mitochondrial RNA polymerase.
  2. Lysosomes drive the piecemeal removal of mitochondrial inner membrane.
  3. MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.
  4. Mitochondrial elongation confers protection against doxorubicin-induced cardiotoxicity.
  5. Reuterin promotes pyroptosis in hepatocellular cancer cells through mtDNA-mediated STING activation and caspase 8 expression.
  6. Restoration of defective oxidative phosphorylation to a subset of neurons prevents mitochondrial encephalopathy.
  7. Adenosine diphosphate released from stressed cells triggers mitochondrial transfer to achieve tissue homeostasis.
  8. Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure.
  9. Misregulation of mitochondrial 6mA promotes the propagation of mutant mtDNA and causes aging in C. elegans.
  10. Unfolded proteins in the mitochondria activate HRI and inhibit mitochondrial protein translation.
  11. Selective induction of senescence in cancer cells through near-infrared light treatment via mitochondrial modulation.
  12. DNA sensors in metabolic and cardiovascular diseases: Molecular mechanisms and therapeutic prospects.
  13. ISGylation enhances double-stranded RNA-induced interferon response and NFκB signaling in fallopian tube epithelial cells.
  14. Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts.
  15. Engineered mitochondria exert potent antitumor immunity as a cancer vaccine platform.
  16. AI-recognized mitochondrial phenotype enables identification of drug targets.
  1. Nat Commun. 2024 Aug 20. 15(1): 7134
    Structural basis for substrate binding and selection by human mitochondrial RNA polymerase.
    Karl Herbine, Ashok R Nayak, Dmitry Temiakov.
      The mechanism by which RNAP selects cognate substrates and discriminates between deoxy and ribonucleotides is of fundamental importance to the fidelity of transcription. Here, we present cryo-EM structures of human mitochondrial transcription elongation complexes that reveal substrate ATP bound in Entry and Insertion Sites. In the Entry Site, the substrate binds along the O helix of the fingers domain of mtRNAP but does not interact with the templating DNA base. Interactions between RNAP and the triphosphate moiety of the NTP in the Entry Site ensure discrimination against nucleosides and their diphosphate and monophosphate derivatives but not against non-cognate rNTPs and dNTPs. Closing of the fingers domain over the catalytic site results in delivery of both the templating DNA base and the substrate into the Insertion Site and recruitment of the catalytic magnesium ions. The cryo-EM data also reveal a conformation adopted by mtRNAP to reject a non-cognate substrate from its active site. Our findings establish a structural basis for substrate binding and suggest a unified mechanism of NTP selection for single-subunit RNAPs.
    DOI:  https://doi.org/10.1038/s41467-024-50817-9
  2. Nature. 2024 Aug 21.
    Lysosomes drive the piecemeal removal of mitochondrial inner membrane.
    Akriti Prashar, Claudio Bussi, Antony Fearns, Mariana I Capurro, Xiaodong Gao, Hiromi Sesaki, Maximiliano G Gutierrez, Nicola L Jones.
      Mitochondrial membranes define distinct structural and functional compartments. Cristae of the inner mitochondrial membrane (IMM) function as independent bioenergetic units that undergo rapid and transient remodelling, but the significance of this compartmentalized organization is unknown1. Using super-resolution microscopy, here we show that cytosolic IMM vesicles, devoid of outer mitochondrial membrane or mitochondrial matrix, are formed during resting state. These vesicles derived from the IMM (VDIMs) are formed by IMM herniation through pores formed by voltage-dependent anion channel 1 in the outer mitochondrial membrane. Live-cell imaging showed that lysosomes in proximity to mitochondria engulfed the herniating IMM and, aided by the endosomal sorting complex required for transport machinery, led to the formation of VDIMs in a microautophagy-like process, sparing the remainder of the organelle. VDIM formation was enhanced in mitochondria undergoing oxidative stress, suggesting their potential role in maintenance of mitochondrial function. Furthermore, the formation of VDIMs required calcium release by the reactive oxygen species-activated, lysosomal calcium channel, transient receptor potential mucolipin 1, showing an interorganelle communication pathway for maintenance of mitochondrial homeostasis. Thus, IMM compartmentalization could allow for the selective removal of damaged IMM sections via VDIMs, which should protect mitochondria from localized injury. Our findings show a new pathway of intramitochondrial quality control.
    DOI:  https://doi.org/10.1038/s41586-024-07835-w
  3. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2402491121
    MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.
    Prottoy Hasan, Elena Berezhnaya, Macarena Rodríguez-Prados, David Weaver, Carmen Bekeova, Benjamin Cartes-Saavedra, Erin Birch, Andreas M Beyer, Janine H Santos, Erin L Seifert, John W Elrod, György Hajnóczky.
      Activating Ca2+-sensitive enzymes of oxidative metabolism while preventing calcium overload that leads to mitochondrial and cellular injury requires dynamic control of mitochondrial Ca2+ uptake. This is ensured by the mitochondrial calcium uptake (MICU)1/2 proteins that gate the pore of the mitochondrial calcium uniporter (mtCU). MICU1 is relatively sparse in the heart, and recent studies claimed the mammalian heart lacks MICU1 gating of mtCU. However, genetic models have not been tested. We find that MICU1 is present in a complex with MCU in nonfailing human hearts. Furthermore, using murine genetic models and pharmacology, we show that MICU1 and MICU2 control cardiac mitochondrial Ca2+ influx, and that MICU1 deletion alters cardiomyocyte mitochondrial calcium signaling and energy metabolism. MICU1 loss causes substantial compensatory changes in the mtCU composition and abundance, increased turnover of essential MCU regulator (EMRE) early on and, later, of MCU, that limit mitochondrial Ca2+ uptake and allow cell survival. Thus, both the primary consequences of MICU1 loss and the ensuing robust compensation highlight MICU1's relevance in the beating heart.
    Keywords:  MICU1; MICU2; calcium; cardiomyocyte; mitochondrial calcium uniporter gating
    DOI:  https://doi.org/10.1073/pnas.2402491121
  4. Biochem Pharmacol. 2024 Aug 17. pii: S0006-2952(24)00478-7. [Epub ahead of print]229 116495
    Mitochondrial elongation confers protection against doxorubicin-induced cardiotoxicity.
    Weibin He, Wenlong He, Xiaopan Chen, Lin Zeng, Lihuan Zeng, Yuanhui Liu, Pengcheng He, Zhongchan Sun.
      Doxorubicin (DOX)-induced cardiac damage remains a leading cause of death amongst cancer survivors. DOX-induced cardiotoxicity (DIC) is mediated by disturbed mitochondrial dynamics, but it remains debated that the mechanisms by which DOX disrupted equilibrium between mitochondrial fission and fusion. In the present study, we observed that DOX induced mitochondrial elongation in multiple cardiovascular cell lines. Mechanically, DOX not only downregulated the mitochondrial fusion proteins including Mitofusin 1/2 (MFN1/2) and Optic atrophy 1 (OPA1), but also induced lower motility of dynamin-related protein 1(Drp1) and its phosphorylation on 637 serine, which could inhibit mitochondrial fission. Interestingly, DOX failed to induce mitochondrial elongation in cardiomyocytes co-treated with protein kinase A (PKA) inhibitor H89 or expressing phosphodeficient Drp1-S637A variants. Besides, carbonyl cyanide 3-chlorophenylhydrazone (CCCP) was able to blocked the mitochondrial elongation induced by DOX treatment, which could be phenocopied by OPA1 knockdown. Therefore, we speculated that DOX inhibited mitochondrial fission and fusion simultaneously, yet enabled mitochondrial fusion dominate the mitochondrial dynamics, resulting in mitochondrial elongation as the main manifestation. Notably, blocking mitochondrial elongation by inhibiting Drp1-S637 phosphorylation or OPA1 knockdown aggravated DOX-induced cardiomyocytes death. Based on these results, we propose a novel mechanistic model that DOX-induced mitochondrial elongation is attributed to the equilibrium disturbance of mitochondrial dynamics, which serves as an adaptive response and confers protection against DIC.
    Keywords:  Cardiotoxicity; Doxorubicin; Fission; Fusion; Mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.bcp.2024.116495
  5. Cancer Lett. 2024 Aug 15. pii: S0304-3835(24)00578-0. [Epub ahead of print]601 217183
    Reuterin promotes pyroptosis in hepatocellular cancer cells through mtDNA-mediated STING activation and caspase 8 expression.
    Lin Cui, Xiaohui Xu, Hui Fan, Xinyan Wan, Qian Chen, Junhui Zhang, Chuntao Tao, Zheng Du, Yitao Wang, Jian Zhang, Jun Zeng, Ying Zhang, Chundong Zhang, Longhao Li, Youquan Bu, Yunlong Lei.
      Hepatocellular carcinoma (HCC) is the most common form of liver cancer with poor prognosis. The available drugs for advanced HCC are limited and substantial therapeutic advances including new drugs and new combination therapies are still in urgent need. In this study, we found that the major metabolite of Lactobacillus reuteri (L. reuteri), reuterin showed great anti-HCC potential and could help in sorafenib treatment. Reuterin treatment impaired mitophagy and caused the aberrant clustering of mitochondrial nucleoids to block mitochondrial DNA (mtDNA) replication and mitochondrial fission, which could promote mtDNA leakage and subsequent STING activation in HCC cells. STING could activate pyroptosis and necroptosis, while reuterin treatment also induced caspase 8 expression to inhibit necroptosis through cleaving RIPK3 in HCC cells. Thus, pyroptosis was the main death form in reuterin-treated HCC cells and STING suppression remarkably rescued the growth inhibitory effect of reuterin and concurrently knockdown caspase 8 synergized to restrain the induction of pyroptosis. In conclusion, our study explains the detailed molecular mechanisms of the antitumor effect of reuterin and reveals its potential to perform as a combinational drug for HCC treatment.
    Keywords:  Hepatocellular carcinoma; Pyroptosis; Reuterin; STING; mtDNA
    DOI:  https://doi.org/10.1016/j.canlet.2024.217183
  6. EMBO Mol Med. 2024 Aug 21.
    Restoration of defective oxidative phosphorylation to a subset of neurons prevents mitochondrial encephalopathy.
    Brittni R Walker, Lise-Michelle Theard, Milena Pinto, Monica Rodriguez-Silva, Sandra R Bacman, Carlos T Moraes.
      Oxidative Phosphorylation (OXPHOS) defects can cause severe encephalopathies and no effective treatment exists for these disorders. To assess the ability of gene replacement to prevent disease progression, we subjected two different CNS-deficient mouse models (Ndufs3/complex I or Cox10/complex IV conditional knockouts) to gene therapy. We used retro-orbitally injected AAV-PHP.eB to deliver the missing gene to the CNS of these mice. In both cases, we observed survival extension from 5-6 to more than 15 months, with no detectable disease phenotypes. Likewise, molecular and cellular phenotypes were mostly recovered in the treated mice. Surprisingly, these remarkable phenotypic improvements were achieved with only ~30% of neurons expressing the transgene from the AAV-PHP.eB vector in the conditions used. These findings suggest that neurons lacking OXPHOS are protected by the surrounding neuronal environment and that partial compensation for neuronal OXPHOS loss can have disproportionately positive effects.
    Keywords:  Gene Therapy; Mitochondria; Mitochondrial Disease; Oxidative Phosphorylation
    DOI:  https://doi.org/10.1038/s44321-024-00111-4
  7. PLoS Biol. 2024 Aug;22(8): e3002753
    Adenosine diphosphate released from stressed cells triggers mitochondrial transfer to achieve tissue homeostasis.
    Hao Li, Hongping Yu, Delin Liu, Peng Liao, Chuan Gao, Jian Zhou, Jialun Mei, Yao Zong, Peng Ding, Meng Yao, Bingqi Wang, Yafei Lu, Yigang Huang, Youshui Gao, Changqing Zhang, Minghao Zheng, Junjie Gao.
      Cell-to-cell mitochondrial transfer has recently been shown to play a role in maintaining physiological functions of cell. We previously illustrated that mitochondrial transfer within osteocyte dendritic network regulates bone tissue homeostasis. However, the mechanism of triggering this process has not been explored. Here, we showed that stressed osteocytes in mice release adenosine diphosphate (ADP), resulting in triggering mitochondrial transfer from healthy osteocytes to restore the oxygen consumption rate (OCR) and to alleviate reactive oxygen species accumulation. Furthermore, we identified that P2Y2 and P2Y6 transduced the ADP signal to regulate osteocyte mitochondrial transfer. We showed that mitochondrial metabolism is impaired in aged osteocytes, and there were more extracellular nucleotides release into the matrix in aged cortical bone due to compromised membrane integrity. Conditioned medium from aged osteocytes triggered mitochondrial transfer between osteocytes to enhance the energy metabolism. Together, using osteocyte as an example, this study showed new insights into how extracellular ADP triggers healthy cells to rescue energy metabolism crisis in stressed cells via mitochondrial transfer in tissue homeostasis.
    DOI:  https://doi.org/10.1371/journal.pbio.3002753
  8. Nat Commun. 2024 Aug 22. 15(1): 7027
    Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure.
    Pawel Lisowski, Selene Lickfett, Agnieszka Rybak-Wolf, Carmen Menacho, Stephanie Le, Tancredi Massimo Pentimalli, Sofia Notopoulou, Werner Dykstra, Daniel Oehler, Sandra López-Calcerrada, Barbara Mlody, Maximilian Otto, Haijia Wu, Yasmin Richter, Philipp Roth, Ruchika Anand, Linda A M Kulka, David Meierhofer, Petar Glazar, Ivano Legnini, Narasimha Swamy Telugu, Tobias Hahn, Nancy Neuendorf, Duncan C Miller, Annett Böddrich, Amin Polzin, Ertan Mayatepek, Sebastian Diecke, Heidi Olzscha, Janine Kirstein, Cristina Ugalde, Spyros Petrakis, Sidney Cambridge, Nikolaus Rajewsky, Ralf Kühn, Erich E Wanker, Josef Priller, Jakob J Metzger, Alessandro Prigione.
      Expansion of the glutamine tract (poly-Q) in the protein huntingtin (HTT) causes the neurodegenerative disorder Huntington's disease (HD). Emerging evidence suggests that mutant HTT (mHTT) disrupts brain development. To gain mechanistic insights into the neurodevelopmental impact of human mHTT, we engineered male induced pluripotent stem cells to introduce a biallelic or monoallelic mutant 70Q expansion or to remove the poly-Q tract of HTT. The introduction of a 70Q mutation caused aberrant development of cerebral organoids with loss of neural progenitor organization. The early neurodevelopmental signature of mHTT highlighted the dysregulation of the protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a transcription factor involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics that was reverted upon overexpression of CHCHD2. Removing the poly-Q tract from HTT normalized CHCHD2 levels and corrected key mitochondrial defects. Hence, mHTT-mediated disruption of human neurodevelopment is paralleled by aberrant neurometabolic programming mediated by dysregulation of CHCHD2, which could then serve as an early interventional target for HD.
    DOI:  https://doi.org/10.1038/s41467-024-51216-w
  9. Cell Metab. 2024 Aug 16. pii: S1550-4131(24)00291-2. [Epub ahead of print]
    Misregulation of mitochondrial 6mA promotes the propagation of mutant mtDNA and causes aging in C. elegans.
    Anne Hahn, Grace Ching Ching Hung, Arnaud Ahier, Chuan-Yang Dai, Ina Kirmes, Brian M Forde, Daniel Campbell, Rachel Shin Yie Lee, Josiah Sucic, Tessa Onraet, Steven Zuryn.
      In virtually all eukaryotes, the mitochondrial DNA (mtDNA) encodes proteins necessary for oxidative phosphorylation (OXPHOS) and RNAs required for their synthesis. The mechanisms of regulation of mtDNA copy number and expression are not completely understood but crucially ensure the correct stoichiometric assembly of OXPHOS complexes from nuclear- and mtDNA-encoded subunits. Here, we detect adenosine N6-methylation (6mA) on the mtDNA of diverse animal and plant species. This modification is regulated in C. elegans by the DNA methyltransferase DAMT-1 and demethylase ALKB-1. Misregulation of mtDNA 6mA through targeted modulation of these activities inappropriately alters mtDNA copy number and transcript levels, impairing OXPHOS function, elevating oxidative stress, and shortening lifespan. Compounding these defects, mtDNA 6mA hypomethylation promotes the cross-generational propagation of a deleterious mtDNA. Together, these results reveal that mtDNA 6mA is highly conserved among eukaryotes and regulates lifespan by influencing mtDNA copy number, expression, and heritable mutation levels in vivo.
    Keywords:  6mA; ROS; aging; epigenetics; heteroplasmy; lifespan; mitochondria; mitochondrial genome; mtDNA; oxidative stress
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.020
  10. Cell Signal. 2024 Aug 19. pii: S0898-6568(24)00321-8. [Epub ahead of print] 111353
    Unfolded proteins in the mitochondria activate HRI and inhibit mitochondrial protein translation.
    Yongshu Wu, Yang Yang, Xiaodong Qin, Zhixiong Zhang, Munib Ullah, Yanmin Li, Zhidong Zhang.
      The mitochondrial unfolded protein response (UPRmt) is triggered through eIF2α phosphorylation in mammals. However, the mechanisms of UPRmt activation and the influence of eIF2α phosphorylation on mitochondrial protein translation remain unclear. In this study, we confirmed that the UPRmt is a rapid and specific stress response that occurs through pharmacological induction of eIF2α phosphorylation, along with the phosphorylation of eIF2α, ATF4, and CHOP. Moreover, with the upregulation of the expression of some chaperones, cytochrome P450 enzymes, and DDIT4, as determined by RNA-Seq and ribosome profiling, eIF2α phosphorylation was found to be essential for the expression of ATF4 and CHOP, after which ATF4 trafficked into the nucleus and initiated CHOP expression. In addition, the generation of ROS and mitochondrial morphology were not affected by the GTPP-induced UPRmt. Furthermore, we investigated the mechanism by which HRI kinase-mediated UPRmt is induced by mitochondrial unfolded proteins via CRISPR-Cas9 technology, mitochondrial recruitment of HRI and interactions with other proteins. Moreover, we confirmed that mitochondrial protein translation and mitochondrial protein import were inhibited through eIF2α phosphorylation with the accumulation of unfolded mitochondrial proteins. These findings reveal the molecular mechanism of the UPRmt and its impact on cellular protein translation, which will offer novel insights into the functions of the UPRmt, including its implications for human disease and pathobiology.
    Keywords:  Heme-regulated inhibitor; Mitochondrial proteostasis; Mitochondrial unfolded protein response; eIF2α phosphorylation
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111353
  11. J Biophotonics. 2024 Aug;17(8): e202400046
    Selective induction of senescence in cancer cells through near-infrared light treatment via mitochondrial modulation.
    I Kalampouka, R R Mould, S W Botchway, A M Mackenzie, A V Nunn, E L Thomas, J D Bell.
      Photobiomodulation, utilising non-ionising light in the visible and near-infrared (NIR) spectrum, has been suggested as a potential method for enhancing tissue repair, reducing inflammation and possibly mitigating cancer-therapy-associated side effects. NIR light is suggested to be absorbed intracellularly, mainly by chromophores within the mitochondria. This study examines the impact of 734 nm NIR light on cellular senescence. Cancer (MCF7 and A549) and non-cancer (MCF10A and IMR-90) cell populations were subjected to 63 mJ/cm2 NIR-light exposure for 6 days. Senescence levels were quantified by measuring active senescence-associated beta-galactosidase. Exposure to NIR light significantly increases senescence levels in cancer (10.0%-203.2%) but not in non-cancer cells (p > 0.05). Changes in senescence were associated with significant modulation of mitochondrial homeostasis, including increased levels of reactive oxygen species (p < 0.05) and mitochondrial membrane potential (p < 0.05) post-NIR-light treatment. These results suggest that NIR light modulates cellular chemistry, arresting the proliferation of cancer cells via senescence induction while sparing non-cancer cells.
    Keywords:  ROS; cancer; mitochondria; near‐infrared light; photobiomodulation; senescence
    DOI:  https://doi.org/10.1002/jbio.202400046
  12. Immunol Rev. 2024 Aug 19.
    DNA sensors in metabolic and cardiovascular diseases: Molecular mechanisms and therapeutic prospects.
    Hyosang Kwak, Ein Lee, Rajendra Karki.
      DNA sensors generally initiate innate immune responses through the production of type I interferons. While extensively studied for host defense against invading pathogens, emerging evidence highlights the involvement of DNA sensors in metabolic and cardiovascular diseases. Elevated levels of modified, damaged, or ectopically localized self-DNA and non-self-DNA have been observed in patients and animal models with obesity, diabetes, fatty liver disease, and cardiovascular disease. The accumulation of cytosolic DNA aberrantly activates DNA signaling pathways, driving the pathological progression of these disorders. This review highlights the roles of specific DNA sensors, such as cyclic AMP-GMP synthase and stimulator of interferon genes (cGAS-STING), absent in melanoma 2 (AIM2), toll-like receptor 9 (TLR9), interferon gamma-inducible protein 16 (IFI16), DNA-dependent protein kinase (DNA-PK), and DEAD-box helicase 41 (DDX41) in various metabolic disorders. We explore how DNA signaling pathways in both immune and non-immune cells contribute to the development of these diseases. Furthermore, we discuss the intricate interplay between metabolic stress and immune responses, offering insights into potential therapeutic targets for managing metabolic and cardiovascular disorders. Understanding the mechanisms of DNA sensor signaling in these contexts provides a foundation for developing novel interventions aimed at mitigating the impact of these pervasive health issues.
    Keywords:  AIM2 and IFI16; DNA‐PK and DDX41; cGAS‐STING pathway; fatty liver and heart diseases; inflammation and cell death; obesity and diabetes
    DOI:  https://doi.org/10.1111/imr.13382
  13. J Biol Chem. 2024 Aug 17. pii: S0021-9258(24)02187-2. [Epub ahead of print] 107686
    ISGylation enhances double-stranded RNA-induced interferon response and NFκB signaling in fallopian tube epithelial cells.
    Vidushi Madaan, Alexandra Kollara, David Spaner, Theodore J Brown.
      Heritable mutations in BRCA1 associate with increased risk of high-grade serous tubo-ovarian cancer (HGSTOC). Non-genetic risk factors associated with this cancer, which arises from fallopian tube epithelial (FTE) cells, suggests a role for repetitive ovulation wherein FTE cells are exposed to inflammatory signaling molecules within follicular fluid. We previously reported increased NFκB and EGFR signaling in BRCA1-deficient primary FTE cells, with follicular fluid exposure further increasing abundance of interferon-stimulated gene (ISG) transcripts, including the ubiquitin-like protein ISG15 and other ISGylation pathway members. Both NFκB and type I interferon signaling are upregulated by stimulation of cGAS-STING or MDA5 and RIGI pattern recognition receptors (PRRs). Since some PRRs and their signal transduction pathway members are ISGylated, we tested the impact of ISG15 and ISGylation on IRF3 and NFκB signaling through cGAS-STING or RIGI and MDA5 activation. Expression of ISG15 or UBA7, the E1-like ISG15 activating enzyme, in immortalized FTE cells was disrupted by CRISPR gene editing. Activation of IRF3 by RIGI or MDA5 but not cGAS-STING was attenuated by loss of either ISG15 or UBA7 and this was reflected by a similar effect on NFκB activation and downstream targets. Loss of ISGylation decreased levels of both MDA5 and RIGI, with knock-down of RIGI but not MDA5, decreasing IRF3 and NFκB activation in parental cells. These finding indicate that ISGylation enhances the ability of dsRNA to activate cytokine release and pro-inflammatory signaling. Further work to explore ISGylation as a target for prevention of HGSTOC in BRCA1 mutation carriers is warranted.
    Keywords:  CRISPR/Cas; ISGylation; NF-kappa B; RIG-I-like receptor; dsRNA; fallopian tube cells; inflammation; innate immunity; interferon; ovarian cancer
    DOI:  https://doi.org/10.1016/j.jbc.2024.107686
  14. PLoS Biol. 2024 Aug;22(8): e3002723
    Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts.
    Weichen Zhou, Kalpita R Karan, Wenjin Gu, Hans-Ulrich Klein, Gabriel Sturm, Philip L De Jager, David A Bennett, Michio Hirano, Martin Picard, Ryan E Mills.
      The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in nonhuman species and recently demonstrated to occur in rare instances from one human generation to the next. Here, we investigated numtogenesis dynamics in humans in 2 ways. First, we quantified Numts in 1,187 postmortem brain and blood samples from different individuals. Compared to circulating immune cells (n = 389), postmitotic brain tissue (n = 798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples, we observed a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex (DLPFC) compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, an increase in the number of brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment (NCI) who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. Second, we tested the dynamic transfer of Numts using a repeated-measures whole-genome sequencing design in a human fibroblast model that recapitulates several molecular hallmarks of aging. These longitudinal experiments revealed a gradual accumulation of 1 Numt every ~13 days. Numtogenesis was independent of large-scale genomic instability and unlikely driven by cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient-derived SURF1-mutant cells exhibiting mtDNA instability accumulated Numts 4.7-fold faster than healthy donors. Combined, our data document spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito-nuclear horizontal gene transfer among human postmitotic tissues produces functionally relevant human Numts over timescales shorter than previously assumed.
    DOI:  https://doi.org/10.1371/journal.pbio.3002723
  15. Cell Mol Immunol. 2024 Aug 20.
    Engineered mitochondria exert potent antitumor immunity as a cancer vaccine platform.
    Jingwen Luo, Fei Mo, Zhe Zhang, Weiqi Hong, Tianxia Lan, Yuan Cheng, Chunju Fang, Zhenfei Bi, Furong Qin, Jingyun Yang, Ziqi Zhang, Xue Li, Haiying Que, Jiayu Wang, Siyuan Chen, Yiming Wu, Li Yang, Jiong Li, Wei Wang, Chong Chen, Xiawei Wei.
      The preferable antigen delivery profile accompanied by sufficient adjuvants favors vaccine efficiency. Mitochondria, which feature prokaryotic characteristics and contain various damage-associated molecular patterns (DAMPs), are easily taken up by phagocytes and simultaneously activate innate immunity. In the current study, we established a mitochondria engineering platform for generating antigen-enriched mitochondria as cancer vaccine. Ovalbumin (OVA) and tyrosinase-related protein 2 (TRP2) were used as model antigens to synthesize fusion proteins with mitochondria-localized signal peptides. The lentiviral infection system was then employed to produce mitochondrial vaccines containing either OVA or TRP2. Engineered OVA- and TRP2-containing mitochondria (OVA-MITO and TRP2-MITO) were extracted and evaluated as potential cancer vaccines. Impressively, the engineered mitochondria vaccine demonstrated efficient antitumor effects when used as both prophylactic and therapeutic vaccines in murine tumor models. Mechanistically, OVA-MITO and TRP2-MITO potently recruited and activated dendritic cells (DCs) and induced a tumor-specific cell-mediated immunity. Moreover, DC activation by mitochondria vaccine critically involves TLR2 pathway and its lipid agonist, namely, cardiolipin derived from the mitochondrial membrane. The results demonstrated that engineered mitochondria are natively well-orchestrated carriers full of immune stimulants for antigen delivery, which could preferably target local dendritic cells and exert strong adaptive cellular immunity. This proof-of-concept study established a universal platform for vaccine construction with engineered mitochondria bearing alterable antigens for cancers as well as other diseases.
    Keywords:  Antitumor immunity; Cardiolipin; Mitochondria vaccine; TLR2
    DOI:  https://doi.org/10.1038/s41423-024-01203-4
  16. Nat Comput Sci. 2024 Aug 22.
    AI-recognized mitochondrial phenotype enables identification of drug targets.
      
    DOI:  https://doi.org/10.1038/s43588-024-00682-9
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