bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2023–04–09
33 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.
  2. Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.
  3. The mitochondrial ATP synthase as an ATP consumer-a surprising therapeutic target.
  4. Novel insights into Parkin-mediated mitochondrial dysfunction and neuroinflammation in Parkinson's disease.
  5. Protein translocation in mitochondria: Sorting out the Toms, Tims, Pams, Sams and Mia.
  6. MitoSwap - Mitophagy partnered with compensatory mitochondrial biogenesis during stem cell differentiation.
  7. Mitochondrial fumarate implicated in inflammation.
  8. Mitochondria in Health, Disease, and Ageing.
  9. TOM complex-independent transport pathway of myoglobin into mitochondria in C2C12 myotubes.
  10. The mitochondrial ribosomal protein mRpL4 regulates Notch signaling.
  11. Role of SIRT3 in mitochondrial biology and its therapeutic implications in neurodegenerative disorders.
  12. Mitochondrial DNA and the STING pathway are required for hepatic stellate cell activation.
  13. NAD+ repletion with niacin counteracts cancer cachexia.
  14. Metaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns.
  15. The Pathological Mechanisms and Novel Therapeutics for Leber's Hereditary Optic Neuropathy.
  16. Quantitative haplotype-resolved analysis of mitochondrial DNA heteroplasmy in Human single oocytes, blastoids, and pluripotent stem cells.
  17. A humanized yeast model reveals dominant-negative properties of neuropathy-associated alanyl-tRNA synthetase mutations.
  18. Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA.
  19. Oligodendrocyte-derived transcellular signaling regulates axonal energy metabolism.
  20. Increased Sphingomyelin and Free Sialic Acid in Cerebrospinal Fluid of Kearns-Sayre Syndrome: New Findings Using Untargeted Metabolomics.
  21. Adiponectin deficiency accelerates brain aging via mitochondria-associated neuroinflammation.
  22. Mediterranean diet and mitochondria: New findings.
  23. CHCHD2 and CHCHD10-related neurodegeneration: molecular pathogenesis and the path to precision therapy.
  24. Explanations for the discrepancy between variant frequency and homozygous disease occurrence: Lessons from Ashkenazi Jewish data.
  25. Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells.
  26. Global determination of reaction rates and lipid turnover kinetics in Mus musculus.
  27. Human umbilical cord-derived mesenchymal stem cells-harvested mitochondrial transplantation improved motor function in TBI models through rescuing neuronal cells from apoptosis and alleviating astrogliosis and microglia activation.
  28. Large-scale mapping and mutagenesis of human transcriptional effector domains.
  29. RNA Delivery to Mitochondria.
  30. Oral supplementation of nicotinamide riboside alters intestinal microbial composition in rats and mice, but not humans.
  31. Mapping out mitochondria.
  32. Metabolomics as a Diagnostic Tool.
  33. mRNA decoding in human is kinetically and structurally distinct from bacteria.
  1. Nat Commun. 2023 Apr 06. 14(1): 1930
    Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.
    Pascale Baden, Maria Jose Perez, Hariam Raji, Federico Bertoli, Stefanie Kalb, María Illescas, Fokion Spanos, Claudio Giuliano, Alessandra Maria Calogero, Marvin Oldrati, Hannah Hebestreit, Graziella Cappelletti, Kathrin Brockmann, Thomas Gasser, Anthony H V Schapira, Cristina Ugalde, Michela Deleidi.
      Mutations in GBA1, the gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher's disease, are the most frequent genetic risk factor for Parkinson's disease (PD). Here, we employ global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from the cytosol into the mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, GCase promotes the maintenance of mitochondrial complex I (CI) integrity and function. Furthermore, GCase interacts with the mitochondrial quality control proteins HSP60 and LONP1. Disease-associated mutations impair CI stability and function and enhance the interaction with the mitochondrial quality control machinery. These findings reveal a mitochondrial role of GCase and suggest that defective CI activity and energy metabolism may drive the pathogenesis of GCase-linked neurodegeneration.
    DOI:  https://doi.org/10.1038/s41467-023-37454-4
  2. EMBO Mol Med. 2023 Apr 04. e16775
    Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.
    Genomics England Research Consortium
      Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.
    Keywords:  Bloom syndrome; TOP3A; mitochondrial disease; mtDNA
    DOI:  https://doi.org/10.15252/emmm.202216775
  3. EMBO J. 2023 Apr 06. e114141
    The mitochondrial ATP synthase as an ATP consumer-a surprising therapeutic target.
    Gabriel E Valdebenito, Anitta R Chacko, Michael R Duchen.
      The mitochondrial F1 Fo -ATP synthase uses a rotary mechanism to synthesise ATP. This mechanism can, however, also operate in reverse, pumping protons at the expense of ATP, with significant potential implications for mitochondrial and age-related diseases. In a recent study, Acin-Perez et al (2023) use an elegant assay to screen compounds for the capacity to selectively inhibit ATP hydrolysis without affecting ATP synthesis. They show that (+)-epicatechin is one such compound and has significant benefits for cell and tissue function in disease models. These findings signpost a novel therapeutic approach for mitochondrial disease.
    DOI:  https://doi.org/10.15252/embj.2023114141
  4. Curr Opin Neurobiol. 2023 Apr 04. pii: S0959-4388(23)00045-4. [Epub ahead of print]80 102720
    Novel insights into Parkin-mediated mitochondrial dysfunction and neuroinflammation in Parkinson's disease.
    Sandro L Pereira, Dajana Grossmann, Sylvie Delcambre, Andreas Hermann, Anne Grünewald.
      Mutations in PRKN cause the second most common genetic form of Parkinson's disease (PD)-a debilitating movement disorder that is on the rise due to population aging in the industrial world. PRKN codes for an E3 ubiquitin ligase that has been well established as a key regulator of mitophagy. Together with PTEN-induced kinase 1 (PINK1), Parkin controls the lysosomal degradation of depolarized mitochondria. But Parkin's functions go well beyond mitochondrial clearance: the versatile protein is involved in mitochondria-derived vesicle formation, cellular metabolism, calcium homeostasis, mitochondrial DNA maintenance, mitochondrial biogenesis, and apoptosis induction. Moreover, Parkin can act as a modulator of different inflammatory pathways. In the current review, we summarize the latest literature concerning the diverse roles of Parkin in maintaining a healthy mitochondrial pool. Moreover, we discuss how these recent discoveries may translate into personalized therapeutic approaches not only for PRKN-PD patients but also for a subset of idiopathic cases.
    Keywords:  Biogenesis; Calcium; Inflammation; Metabolism; Mitochondria; Mitophagy; PINK1; Parkin; Parkinson's disease; mtDNA
    DOI:  https://doi.org/10.1016/j.conb.2023.102720
  5. FEBS Lett. 2023 Apr 05.
    Protein translocation in mitochondria: Sorting out the Toms, Tims, Pams, Sams and Mia.
    Johannes M Herrmann, Yury Bykov.
      Mitochondria contain 902 (yeast) to 1.136 (mouse, humans) verified proteins. Except for a very small number of mitochondrially encoded core components of the respiratory chain, mitochondrial proteins are encoded by nuclear genes and synthesized in the cytosol. Different import pathways direct proteins to their respective mitochondrial subcompartment (outer membrane, intermembrane space (IMS), inner membrane and matrix). Specific targeting signals in their sequence direct proteins to their target destination and allow the proteins to embark on their respective import pathway. The main import pathways are shown here on the poster and are introduced in the following, using the mitochondrial import system of the baker's yeast Saccharomyces cerevisiae as example. However, the mitochondrial import system of mammalian cells is highly similar and deviates only in minor aspects. Even the mitochondrial import machineries of less closely related eukaryotes, such as plants and trypanosomes, are very similar and adhere to the same general principles.
    Keywords:  Mitochondria; Protein Import; Protein translocation; Translocase of the inner membrane; Translocase of the outer membrane
    DOI:  https://doi.org/10.1002/1873-3468.14614
  6. Autophagy Rep. 2022 ;1(1): 210-213
    MitoSwap - Mitophagy partnered with compensatory mitochondrial biogenesis during stem cell differentiation.
    Priyanka Gajwani, Jalees Rehman.
      Differentiating stem cells must adapt their mitochondrial metabolism to fit the needs of the mature differentiated cell. In a recent study, we observed that during differentiation to an endothelial phenotype, pluripotent stem cell mitochondria are removed by mitophagy, triggering compensatory mitochondrial biogenesis to replenish the mitochondrial pool. We identified the mitochondrial phosphatase PGAM5 as the link between mitophagy and transcription of the mitochondrial biogenesis regulator PPARGC1A/PGC1α in the nucleus. Swapping of mitochondria through the coupled processes of mitophagy and mitochondrial biogenesis lead to enhanced metabolic reprogramming in the differentiated cell.
    Keywords:  CTNNB1/β-catenin; PINK1; PPARGC1A/PGC1α; differentiation; endothelium; mitochondrial biogenesis; mitofusin 2; mitophagy; stem cells
    DOI:  https://doi.org/10.1080/27694127.2022.2071549
  7. Nat Rev Rheumatol. 2023 Apr 06.
    Mitochondrial fumarate implicated in inflammation.
    Sarah Onuora.
      
    DOI:  https://doi.org/10.1038/s41584-023-00963-z
  8. Physiol Rev. 2023 Apr 06.
    Mitochondria in Health, Disease, and Ageing.
    John S Harrington, Stefan W Ryter, Maria Plataki, David R Price, Augustine M K Choi.
      Mitochondria are well-known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. While oxidative phosphorylation may be their most important function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell-death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.
    Keywords:  Apoptosis; Inflammation; Mitochondria; Mitochondrial Dysfunction; Mitophagy
    DOI:  https://doi.org/10.1152/physrev.00058.2021
  9. Physiol Rep. 2023 Apr;11(7): e15632
    TOM complex-independent transport pathway of myoglobin into mitochondria in C2C12 myotubes.
    Rikuhide Koma, Tsubasa Shibaguchi, Yuhei Araiso, Tatsuya Yamada, Yudai Nonaka, Thomas Jue, Kazumi Masuda.
      Recently, we found that myoglobin (Mb) localizes in both the cytosol and mitochondrial intermembrane space in rodent skeletal muscle. Most proteins of the intermembrane space pass through the outer mitochondrial membrane via the translocase of the outer membrane (TOM) complex. However, whether the TOM complex imports Mb remains unknown. The purpose of this study was to investigate the involvement of the TOM complex in Mb import into the mitochondria. A proteinase K protection assay of mitochondria from C2C12 myotubes confirmed that Mb integrated into the mitochondria. An immunoprecipitation assay verified the interaction of Mb and TOM complex receptors (Tom20, Tom70) in isolated mitochondria. The assay showed a clear interaction of Mb with Tom20 and Tom70. A knockdown experiment using siRNA for TOM complex receptors (Tom20, Tom70) and TOM complex channel (Tom40) did not alter the amount of Mb expression in the mitochondrial fraction. These results suggested that Mb does not necessarily require the TOM complex for mitochondrial import of Mb. Although the physiological role of Mb interactions with TOM complex receptors remains unclear, further studies are needed to clarify how Mb enters the mitochondria independently of the TOM complex.
    Keywords:  Tom20; Tom40; Tom70; skeletal muscle
    DOI:  https://doi.org/10.14814/phy2.15632
  10. EMBO Rep. 2023 Apr 03. e55764
    The mitochondrial ribosomal protein mRpL4 regulates Notch signaling.
    Dongqing Mo, Chenglin Liu, Yao Chen, Xinkai Cheng, Jie Shen, Long Zhao, Junzheng Zhang.
      Mitochondrial ribosomal proteins (MRPs) assemble as specialized ribosome to synthesize mtDNA-encoded proteins, which are essential for mitochondrial bioenergetic and metabolic processes. MRPs are required for fundamental cellular activities during animal development, but their roles beyond mitochondrial protein translation are poorly understood. Here, we report a conserved role of the mitochondrial ribosomal protein L4 (mRpL4) in Notch signaling. Genetic analyses demonstrate that mRpL4 is required in the Notch signal-receiving cells to permit target gene transcription during Drosophila wing development. We find that mRpL4 physically and genetically interacts with the WD40 repeat protein wap and activates the transcription of Notch signaling targets. We show that human mRpL4 is capable of replacing fly mRpL4 during wing development. Furthermore, knockout of mRpL4 in zebrafish leads to downregulated expression of Notch signaling components. Thus, we have discovered a previously unknown function of mRpL4 during animal development.
    Keywords:   Drosophila ; Notch; mitochondrial ribosomal protein L4; wap; zebrafish
    DOI:  https://doi.org/10.15252/embr.202255764
  11. Drug Discov Today. 2023 Apr 05. pii: S1359-6446(23)00099-5. [Epub ahead of print] 103583
    Role of SIRT3 in mitochondrial biology and its therapeutic implications in neurodegenerative disorders.
    Yogesh Mishra, Ravinder Kumar Kaundal.
      Sirtuin 3 (SIRT3), a mitochondrial deacetylase expressed preferentially in high-metabolic-demand tissues including the brain, requires NAD+ as a cofactor for catalytic activity. It regulates various processes such as energy homeostasis, redox balance, mitochondrial quality control, mitochondrial unfolded protein response (UPRmt), biogenesis, dynamics and mitophagy by altering protein acetylation status. Reduced SIRT3 expression or activity causes hyperacetylation of hundreds of mitochondrial proteins, which has been linked with neurological abnormalities, neuro-excitotoxicity and neuronal cell death. A body of evidence has suggested, SIRT3 activation as a potential therapeutic modality for age-related brain abnormalities and neurodegenerative disorders.
    Keywords:  SIRT3; SIRT3 activators; acetylome; aging; deacetylation; exercise; mitochondria; neurodegenerative disorders; neurogenesis; oxidative stress
    DOI:  https://doi.org/10.1016/j.drudis.2023.103583
  12. Hepatology. 2023 Apr 05.
    Mitochondrial DNA and the STING pathway are required for hepatic stellate cell activation.
    Suyavaran Arumugam, Binghua Li, Sri Lakshmi Tejaswi Boodapati, Michael Harris Nathanson, Beicheng Sun, Xinshou Ouyang, Wajahat Zafar Mehal.
       BACKGROUND AND AIMS: TGF-β induces multiple structural and functional changes in quiescent hepatic stellate cells (HSC) including an increase in proliferation, mitochondrial mass, and matrix deposition. HSC trans-differentiation requires significant bioenergetic capacity and it is not known how TGF-β mediated transcriptional up-regulation is coordinated with the bioenergetic capacity of HSC.
    APPROACH AND RESULTS: Mitochondria are key bioenergetic organelles and here we report that TGF-β induces release of mitochondrial DNA (mtDNA) from healthy HSC via voltage-dependent anions channels (VDACs), with the formation of a mtDNA-CAP on the external mitochondrial membrane. This stimulates organization of cytosolic cGAS onto the mtDNA-CAP, and subsequent activation of the cGAS-STING-IRF3 pathway. TGF-β is unable to induce conversion of HSC from a quiescent to a trans-differentiated phenotype in the absence of mtDNA, VDAC or STING. Trans-differentiation by TGF-β is blocked by a STING inhibitor which also reduces liver fibrosis prophylactically and therapeutically.
    CONCLUSION: We have identified a pathway which requires the presence of functional mitochondria for TGF-β to mediate HSC transcriptional regulation and transdifferentiation, and therefore provides a key link between bioenergetic capacity of HSC and signals for transcriptional up-regulation of genes of anabolic pathways.
    DOI:  https://doi.org/10.1097/HEP.0000000000000388
  13. Nat Commun. 2023 Apr 03. 14(1): 1849
    NAD+ repletion with niacin counteracts cancer cachexia.
    Marc Beltrà, Noora Pöllänen, Claudia Fornelli, Kialiina Tonttila, Myriam Y Hsu, Sandra Zampieri, Lucia Moletta, Samantha Corrà, Paolo E Porporato, Riikka Kivelä, Carlo Viscomi, Marco Sandri, Juha J Hulmi, Roberta Sartori, Eija Pirinen, Fabio Penna.
      Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD+) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirm that depletion of NAD+ and downregulation of Nrk2, an NAD+ biosynthetic enzyme, are common features of severe cachexia in different mouse models. Testing NAD+ repletion therapy in cachectic mice reveals that NAD+ precursor, vitamin B3 niacin, efficiently corrects tissue NAD+ levels, improves mitochondrial metabolism and ameliorates cancer- and chemotherapy-induced cachexia. In a clinical setting, we show that muscle NRK2 is downregulated in cancer patients. The low expression of NRK2 correlates with metabolic abnormalities underscoring the significance of NAD+ in the pathophysiology of human cancer cachexia. Overall, our results propose NAD+ metabolism as a therapy target for cachectic cancer patients.
    DOI:  https://doi.org/10.1038/s41467-023-37595-6
  14. Nat Cell Biol. 2023 Apr 03.
    Metaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns.
    Jordan A Berg, Youjia Zhou, Yeyun Ouyang, Ahmad A Cluntun, T Cameron Waller, Megan E Conway, Sara M Nowinski, Tyler Van Ry, Ian George, James E Cox, Bei Wang, Jared Rutter.
      Metabolism is intertwined with various cellular processes, including controlling cell fate, influencing tumorigenesis, participating in stress responses and more. Metabolism is a complex, interdependent network, and local perturbations can have indirect effects that are pervasive across the metabolic network. Current analytical and technical limitations have long created a bottleneck in metabolic data interpretation. To address these shortcomings, we developed Metaboverse, a user-friendly tool to facilitate data exploration and hypothesis generation. Here we introduce algorithms that leverage the metabolic network to extract complex reaction patterns from data. To minimize the impact of missing measurements within the network, we introduce methods that enable pattern recognition across multiple reactions. Using Metaboverse, we identify a previously undescribed metabolite signature that correlated with survival outcomes in early stage lung adenocarcinoma patients. Using a yeast model, we identify metabolic responses suggesting an adaptive role of citrate homeostasis during mitochondrial dysfunction facilitated by the citrate transporter, Ctp1. We demonstrate that Metaboverse augments the user's ability to extract meaningful patterns from multi-omics datasets to develop actionable hypotheses.
    DOI:  https://doi.org/10.1038/s41556-023-01117-9
  15. J Chin Med Assoc. 2023 Apr 10.
    The Pathological Mechanisms and Novel Therapeutics for Leber's Hereditary Optic Neuropathy.
    Yi-Ping Yang, Shania Foustine, Yu-Jer Hsiao, En-Tung Tsai, Fu-Ting Tsai, Chia-Lin Wang, Yu-Ling Ko, Hsiao-Yun Tai, Yi-Ching Tsai, Chang-Hao Yang, Yun-Ju Fu, An-Guor Wang, Yueh Chien.
      Optic neuropathies were estimated to affect 115 in 100,000 population in 2018. Leber's Hereditary Optic Neuropathy (LHON) as one of such optic neuropathy diseases that was first identified in 1871 and can be defined as a hereditary mitochondrial disease. LHON is associated with three mtDNA point mutations which are G11778A, T14484, and G3460A that affect the NADH dehydrogenase subunits of 4, 6, and 1, respectively. However, in most cases, only one point mutation is involved. Generally, in manifestation of the disease, there are no symptoms until the terminal dysfunction in the optic nerve is observed. Due to the mutations, nicotinamide adenine dinucleotide (NADH) dehydrogenase or complex I is absent and thus ATP production is stopped. This further causes the generation of reactive oxygen species (ROS) and retina ganglion cells (RGC) apoptosis. Aside from the mutations, there are several environmental factors such as smoking and alcohol consumption that can be pointed out as the risk factors of LHON. Nowadays, gene therapy has been intensively studied for LHON treatment. Disease models using human induced pluripotent stem cells (hiPSCs) have been utilized for LHON research.
    DOI:  https://doi.org/10.1097/JCMA.0000000000000927
  16. Nucleic Acids Res. 2023 Apr 04. pii: gkad209. [Epub ahead of print]
    Quantitative haplotype-resolved analysis of mitochondrial DNA heteroplasmy in Human single oocytes, blastoids, and pluripotent stem cells.
    Chongwei Bi, Lin Wang, Yong Fan, Baolei Yuan, Samhan Alsolami, Yingzi Zhang, Pu-Yao Zhang, Yanyi Huang, Yang Yu, Juan Carlos Izpisua Belmonte, Mo Li.
      Maternal mitochondria are the sole source of mtDNA for every cell of the offspring. Heteroplasmic mtDNA mutations inherited from the oocyte are a common cause of metabolic diseases and associated with late-onset diseases. However, the origin and dynamics of mtDNA heteroplasmy remain unclear. We used our individual Mitochondrial Genome sequencing (iMiGseq) technology to study mtDNA heterogeneity, quantitate single nucleotide variants (SNVs) and large structural variants (SVs), track heteroplasmy dynamics, and analyze genetic linkage between variants at the individual mtDNA molecule level in single oocytes and human blastoids. Our study presented the first single-mtDNA analysis of the comprehensive heteroplasmy landscape in single human oocytes. Unappreciated levels of rare heteroplasmic variants well below the detection limit of conventional methods were identified in healthy human oocytes, of which many are reported to be deleterious and associated with mitochondrial disease and cancer. Quantitative genetic linkage analysis revealed dramatic shifts of variant frequency and clonal expansions of large SVs during oogenesis in single-donor oocytes. iMiGseq of a single human blastoid suggested stable heteroplasmy levels during early lineage differentiation of naïve pluripotent stem cells. Therefore, our data provided new insights of mtDNA genetics and laid a foundation for understanding mtDNA heteroplasmy at early stages of life.
    DOI:  https://doi.org/10.1093/nar/gkad209
  17. Hum Mol Genet. 2023 Apr 03. pii: ddad054. [Epub ahead of print]
    A humanized yeast model reveals dominant-negative properties of neuropathy-associated alanyl-tRNA synthetase mutations.
    Rebecca Meyer-Schuman, Sheila Marte, Tyler J Smith, Shawna M E Feely, Marina Kennerson, Garth Nicholson, Mike E Shy, Kristin S Koutmou, Anthony Antonellis.
      Aminoacyl-tRNA synthetases (ARSs) are essential enzymes that ligate tRNA molecules to cognate amino acids. Heterozygosity for missense variants or small in-frame deletions in six ARS genes causes dominant axonal peripheral neuropathy. These pathogenic variants reduce enzyme activity without significantly decreasing protein levels and reside in genes encoding homo-dimeric enzymes. These observations raise the possibility that neuropathy-associated ARS variants exert a dominant-negative effect, reducing overall ARS activity below a threshold required for peripheral nerve function. To test such variants for dominant-negative properties, we developed a humanized yeast assay to co-express pathogenic human alanyl-tRNA synthetase (AARS1) mutations with wild-type human AARS1. We show that multiple loss-of-function AARS1 mutations impair yeast growth through an interaction with wild-type AARS1, but that reducing this interaction rescues yeast growth. This suggests that neuropathy-associated AARS1 variants exert a dominant-negative effect, which supports a common, loss-of-function mechanism for ARS-mediated dominant peripheral neuropathy.
    DOI:  https://doi.org/10.1093/hmg/ddad054
  18. Free Radic Biol Med. 2023 Apr 01. pii: S0891-5849(23)00368-4. [Epub ahead of print]
    Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA.
    Mansoor Hussain, Xixia Chu, Burcin Duan Sahbaz, Samuel Gray, Komal Pekhale, Jae-Hyeon Park, Deborah L Croteau, Vilhelm A Bohr.
      Aging is accompanied by a decline in DNA repair efficiency, which leads to the accumulation of different types of DNA damage. Age-associated chronic inflammation and generation of reactive oxygen species exacerbate the aging process and age-related chronic disorders. These inflammatory processes establish conditions that favor accumulation of DNA base damage, especially 8-oxo-7,8 di-hydroguanine (8-oxoG), which in turn contributes to various age associated diseases. 8-oxoG is repaired by 8-oxoG glycosylase1 (OGG1) through the base excision repair (BER) pathway. OGG1 is present in both the cell nucleus and in mitochondria. Mitochondrial OGG1 has been implicated in mitochondrial DNA repair and increased mitochondrial function. Using transgenic mouse models and cell lines that have been engineered to have enhanced expression of mitochondria-targeted OGG1 (mtOGG1), we show that elevated levels of mtOGG1 in mitochondria can reverse aging-associated inflammation and improve functions. Old male mtOGG1Tg mice show decreased inflammation response, decreased TNFα levels and multiple pro-inflammatory cytokines. Moreover, we observe that male mtOGG1Tg mice show resistance to STING activation. Interestingly, female mtOGG1Tg mice did not respond to mtOGG1 overexpression. Further, HMC3 cells expressing mtOGG1 display decreased release of mtDNA into the cytoplasm after lipopolysacchride induction and regulate inflammation through the pSTING pathway. Also, increased mtOGG1 expression reduced LPS-induced loss of mitochondrial functions. These results suggest that mtOGG1 regulates age-associated inflammation by controlling release of mtDNA into the cytoplasm.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.03.262
  19. Curr Opin Neurobiol. 2023 Apr 05. pii: S0959-4388(23)00047-8. [Epub ahead of print]80 102722
    Oligodendrocyte-derived transcellular signaling regulates axonal energy metabolism.
    Sunan Li, Zu-Hang Sheng.
      The unique morphology and functionality of central nervous system (CNS) neurons necessitate specialized mechanisms to maintain energy metabolism throughout long axons and extensive terminals. Oligodendrocytes (OLs) enwrap CNS axons with myelin sheaths in a multilamellar fashion. Apart from their well-established function in action potential propagation, OLs also provide intercellular metabolic support to axons by transferring energy metabolites and delivering exosomes consisting of proteins, lipids, and RNAs. OL-derived metabolic support is crucial for the maintenance of axonal integrity; its dysfunction has emerged as an important player in neurological disorders that are associated with axonal energy deficits and degeneration. In this review, we discuss recent advances in how these transcellular signaling pathways maintain axonal energy metabolism in health and neurological disorders.
    Keywords:  ATP supply; Axonal bioenergetics; Energy metabolism; Exosome; Glycolysis; Metabolite shuttling; Mitochondria; Myelin; Neurodegeneration; Oligodendrocyte
    DOI:  https://doi.org/10.1016/j.conb.2023.102722
  20. Pediatr Neurol. 2023 Mar 04. pii: S0887-8994(23)00064-4. [Epub ahead of print]143 68-76
    Increased Sphingomyelin and Free Sialic Acid in Cerebrospinal Fluid of Kearns-Sayre Syndrome: New Findings Using Untargeted Metabolomics.
    Cathrin Lytomt Salvador, Mari Oppebøen, Anja Østeby Vassli, Helle Cecilie Viekilde Pfeiffer, Kristin Nielsen Varhaug, Katja Benedikte Prestø Elgstøen, Mazyar Yazdani.
       BACKGROUND: Kearns-Sayre syndrome (KSS) is caused by duplications and/or deletions of mitochondrial DNA (mtDNA) and is typically diagnosed based on a classic triad of symptoms with chronic progressive external ophthalmoplegia (CPEO), retinitis pigmentosa, and onset before age 20 years. The present study aimed to diagnose two patients, on suspicion of KSS.
    METHODS: One of the patients went through a diagnostic odyssey, with normal results from several mtDNA analyses, both in blood and muscle, before the diagnosis was confirmed genetically.
    RESULTS: Two patients presented increased tau protein and low 5-methyltetrahydrofolate (5-MTHF) levels in the cerebrospinal fluid (CSF). Untargeted metabolomics on CSF samples also showed an increase in the levels of free sialic acid and sphingomyelin C16:0 (d18:1/C16:0), compared with four control groups (patients with mitochondrial disorders, nonmitochondrial disorders, low 5-MTHF, or increased tau proteins).
    CONCLUSIONS: It is the first time that elevated sphingomyelin C16:0 (d18:1/C16:0) and tau protein in KSS are reported. Using an untargeted metabolomics approach and standard laboratory methods, the study could shed new light on metabolism in KSS to better understand its complexity. In addition, the findings may suggest the combination of elevated free sialic acid, sphingomyelin C16:0 (d18:1/C16:0), and tau protein as well as low 5-MTHF as new biomarkers in the diagnostics of KSS.
    Keywords:  5-Methyltetrahydrofolate; CAFSA; Kearns-Sayre syndrome; Metabolomics; Mitochondrial DNA; Sialic acid; Sphingomyelin; Tau protein
    DOI:  https://doi.org/10.1016/j.pediatrneurol.2023.02.016
  21. Immun Ageing. 2023 Apr 01. 20(1): 15
    Adiponectin deficiency accelerates brain aging via mitochondria-associated neuroinflammation.
    Kaiwu He, Lulin Nie, Tahir Ali, Zizhen Liu, Weifen Li, Ruyan Gao, Zena Zhang, Jianjun Liu, Zhongliang Dai, Yongmei Xie, Zaijun Zhang, Gongping Liu, Ming Dong, Zhi-Jian Yu, Shupeng Li, Xifei Yang.
       BACKGROUND: A wide spectrum of changes occurs in the brain with age, from molecular to morphological aspects, and inflammation accompanied by mitochondria dysfunction is one of the significant factors associated with age. Adiponectin (APN), an essential adipokine in glucose and lipid metabolism, is involved in the aging; however, its role in brain aging has not been adequately explored. Here, we aimed to explore the relationship between APN deficiency and brain aging using multiple biochemical and pharmacological methods to probe APN in humans, KO mice, primary microglia, and BV2 cells.
    RESULTS: We found that declining APN levels in aged human subjects correlated with dysregulated cytokine levels, while APN KO mice exhibited accelerated aging accompanied by learning and memory deficits, anxiety-like behaviors, neuroinflammation, and immunosenescence. APN-deficient mice displayed aggravated mitochondrial dysfunction and HDAC1 upregulation. In BV2 cells, the APN receptor agonist AdipoRon alleviated the mitochondrial deficits and aging markers induced by rotenone or antimycin A. HDAC1 antagonism by Compound 60 (Cpd 60) improved mitochondrial dysfunction and age-related inflammation, as validated in D-galactose-treated APN KO mice.
    CONCLUSION: These findings indicate that APN is a critical regulator of brain aging by preventing neuroinflammation associated with mitochondrial impairment via HDAC1 signaling.
    Keywords:  Adiponectin; Aging; BV2 Cells; HDAC1; Mitochondria; Neuroinflammation
    DOI:  https://doi.org/10.1186/s12979-023-00339-7
  22. Exp Gerontol. 2023 Apr 05. pii: S0531-5565(23)00086-4. [Epub ahead of print]176 112165
    Mediterranean diet and mitochondria: New findings.
    Francesco Pollicino, Nicola Veronese, Ligia J Dominguez, Mario Barbagallo.
      Mitochondria are subcellular organelles known for their central role in several energetic processes. Accumulating evidence supports a key role for mitochondria in the physiological response to both acute and chronic stress exposure, and, ultimately, the biological embedding of adversity in health and psychological functioning that increases the interest of these organelles in several medical conditions typical of older people. At the same time, Mediterranean diet (MedDiet) seems to affect the function of mitochondria further justifying the role of this diet in lowering the risk of negative health outcomes. In this review, we have elucidated the role of mitochondria in human diseases including the fundamental role in stress, aging, and neuropsychiatric and metabolic disorders. Overall, MedDiet can limit the production of free radicals, being rich in polyphenols. Moreover, MedDiet reduced mitochondrial reactive oxygen species (mtROS) production and ameliorated mitochondrial damage and apoptosis. Similarly, whole grains can maintain the mitochondrial respiration and membrane potential, finally improving mitochondrial function. Other components of MedDiet can have anti-inflammatory effects, again modulating mitochondrial function. For example, delphinidin (a flavonoid present in red wine and berries) restored the elevated level of mitochondrial respiration, mtDNA content, and complex IV activity; similarly, resveratrol and lycopene, present in grapefruits and tomatoes, exerted an anti-inflammatory effect modulating mitochondrial enzymes. Altogether, these findings support the notion that several positive effects of MedDiet can be mediated by a modulation in mitochondrial function indicating the necessity of further studies in human beings for finally confirming these findings.
    Keywords:  Dementia; Inflammation; Mediterranean diet; Metabolic syndrome; Mitochondria; Stress
    DOI:  https://doi.org/10.1016/j.exger.2023.112165
  23. Biochem Soc Trans. 2023 Apr 06. pii: BST20221365. [Epub ahead of print]
    CHCHD2 and CHCHD10-related neurodegeneration: molecular pathogenesis and the path to precision therapy.
    Mario K Shammas, Tzu-Hsiang Huang, Derek P Narendra.
      In the last decade, dominant mutations in the mitochondrial protein CHCHD10 (p.R15L and p.S59L) and its paralog CHCHD2 (p.T61I) were shown to cause familial amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), respectively, with phenotypes that often resemble the idiopathic forms of the diseases. Different mutations in CHCHD10 cause additional neuromuscular disorders, including the lower motor neuron disease Spinal Muscular Atrophy Jokela type (SMAJ) (p.G66V) and autosomal dominant isolated mitochondrial myopathy (IMMD) (p.G58R). Modeling these disorders is revealing how mitochondrial dysfunction may drive ALS and PD pathogenesis by a gain of function mechanism, driven by protein misfolding of CHCHD2 and CHCHD10 into toxic species. It is also laying the groundwork for precision therapy of CHCHD2/CHCHD10-related neurodegeneration. In this review, we address the normal function of CHCHD2 and CHCHD10, the mechanisms of their disease pathogenesis, the strong genotype-phenotype correlations that have emerged for CHCHD10, and potential therapeutic strategies for these disorders.
    Keywords:  Parkinson's disease; amyotrophic lateral sclerosis; antisense oligo; mitochondrial dysfunction; stress response
    DOI:  https://doi.org/10.1042/BST20221365
  24. Eur J Med Genet. 2023 Apr 05. pii: S1769-7212(23)00071-X. [Epub ahead of print] 104765
    Explanations for the discrepancy between variant frequency and homozygous disease occurrence: Lessons from Ashkenazi Jewish data.
    Joël Zlotogora, Tamar Harel, Vardiella Meiner.
      Ample data on recessive disorders among Ashkenazi Jews has been gathered and published through the years. The opportunity to integrate molecular records analyzed in actual affected individuals with data derived from population-documented frequencies enables to compare these figures. We reviewed assumed pathogenic variants reported among patients in the Israeli medical genetic database (IMGD) with a carrier frequency of 1% or more among Ashkenazi Jews in gnomAD. Among the 60 assumed pathogenic variants recorded in IMGD, 15 (25%) had either a disease incidence considerably lower than expected by the calculated carrier frequency (12 variants), or the variant was not characterized in Ashkenazi Jewish patients (three variants). Possible explanations for the rarity or absence of affected individuals despite high carrier frequency include embryonic lethality, clinical variability, and incomplete and age-related penetrance, in addition to the existence of additional assumed pathogenic variants on the founder haplotype, hypomorphic variants or digenic inheritance. The discrepancy in actual versus expected number of patients calls for caution upon designing and choosing targeted genes and recessive mutations for carrier screening.
    Keywords:  Ashkenazi Jews; Founder mutations; gnomAD
    DOI:  https://doi.org/10.1016/j.ejmg.2023.104765
  25. Nat Metab. 2023 Apr 03.
    Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells.
    Alanna C Green, Petra Marttila, Nicole Kiweler, Christina Chalkiadaki, Elisée Wiita, Victoria Cookson, Antoine Lesur, Kim Eiden, François Bernardin, Karl S A Vallin, Sanjay Borhade, Maeve Long, Elahe Kamali Ghahe, Julio J Jiménez-Alonso, Ann-Sofie Jemth, Olga Loseva, Oliver Mortusewicz, Marianne Meyers, Elodie Viry, Annika I Johansson, Ondřej Hodek, Evert Homan, Nadilly Bonagas, Louise Ramos, Lars Sandberg, Morten Frödin, Etienne Moussay, Ana Slipicevic, Elisabeth Letellier, Jérôme Paggetti, Claus Storgaard Sørensen, Thomas Helleday, Martin Henriksson, Johannes Meiser.
      Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.
    DOI:  https://doi.org/10.1038/s42255-023-00771-5
  26. Cell Metab. 2023 Apr 04. pii: S1550-4131(23)00085-2. [Epub ahead of print]35(4): 711-721.e4
    Global determination of reaction rates and lipid turnover kinetics in Mus musculus.
    Qishan Chen, Hu Li, He Tian, Sin Man Lam, Yilie Liao, Ziyin Zhang, Manyuan Dong, Shaoru Chen, Yuxiao Yao, Jiemiao Meng, Yong Zhang, Lemin Zheng, Zhuo-Xian Meng, Weiping Han, Guanghou Shui, Dahai Zhu, Suneng Fu.
      Metabolism is fundamental to life, but measuring metabolic reaction rates remains challenging. Here, we applied C13 fluxomics to monitor the metabolism of dietary glucose carbon in 12 tissues, 9 brain compartments, and over 1,000 metabolite isotopologues over a 4-day period. The rates of 85 reactions surrounding central carbon metabolism are determined with elementary metabolite unit (EMU) modeling. Lactate oxidation, not glycolysis, occurs at a comparable pace with the tricarboxylic acid cycle (TCA), supporting lactate as the primary fuel. We expand the EMU framework to track and quantify metabolite flows across tissues. Specifically, multi-organ EMU simulation of uridine metabolism shows that tissue-blood exchange, not synthesis, controls nucleotide homeostasis. In contrast, isotopologue fingerprinting and kinetic analyses reveal the brown adipose tissue (BAT) having the highest palmitate synthesis activity but no apparent contribution to circulation, suggesting a tissue-autonomous synthesis-to-burn mechanism. Together, this study demonstrates the utility of dietary fluxomics for kinetic mapping in vivo and provides a rich resource for elucidating inter-organ metabolic cross talk.
    Keywords:  dietary fluxomics; elementary metabolite units; inter-organ metabolite flow; multi-organ EMU modeling
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.007
  27. Int Immunopharmacol. 2023 Apr 02. pii: S1567-5769(23)00427-7. [Epub ahead of print]118 110106
    Human umbilical cord-derived mesenchymal stem cells-harvested mitochondrial transplantation improved motor function in TBI models through rescuing neuronal cells from apoptosis and alleviating astrogliosis and microglia activation.
    Chia Bamshad, Mehryar Habibi Roudkenar, Mahmoud Abedinzade, Shahrokh Yousefzadeh Chabok, Zahra Pourmohammadi-Bejarpasi, Nima Najafi-Ghalehlou, Tomoaki Sato, Kazuo Tomita, Ali Jahanian-Najafabadi, Alireza Feizkhah, Amaneh Mohammadi Roushandeh.
      Each year, traumatic brain injury (TBI) causes a high rate of mortality throughout the world and those who survive have lasting disabilities. Given that the brain is a particularly dynamic organ with a high energy consumption rate, the inefficiency of current TBI treatment options highlights the necessity of repairing damaged brain tissue at the cellular and molecular levels, which according to research is aggravated due to ATP deficiency and reactive oxygen species surplus. Taking into account that mitochondria contribute to generating energy and controlling cellular stress, mitochondrial transplantation as a new treatment approach has lately reduced complications in a number of diseases by supplying healthy and functional mitochondria to the damaged tissue. For this reason, in this study, we used this technique to transplant human umbilical cord-derived mesenchymal stem cells (hUC-MSCs)-derived mitochondria as a suitable source for mitochondrial isolation into rat models of TBI to examine its therapeutic benefit and the results showed that the successful mitochondrial internalisation in the neuronal cells significantly reduced the number of brain cells undergoing apoptosis, alleviated astrogliosis and microglia activation, retained normal brain morphology and cytoarchitecture, and improved sensorimotor functions in a rat model of TBI. These data indicate that human umbilical cord-derived mesenchymal stem cells-isolated mitochondrial transplantation improves motor function in a rat model of TBI via rescuing neuronal cells from apoptosis and alleviating astrogliosis and microglia activation, maybe as a result of restoring the lost mitochondrial content.
    Keywords:  Apoptosis; Mesenchymal stem cells; Mitochondrial transplantation; Sensorimotor behaviour; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.intimp.2023.110106
  28. Nature. 2023 Apr 05.
    Large-scale mapping and mutagenesis of human transcriptional effector domains.
    Nicole DelRosso, Josh Tycko, Peter Suzuki, Cecelia Andrews, Aradhana, Adi Mukund, Ivan Liongson, Connor Ludwig, Kaitlyn Spees, Polly Fordyce, Michael C Bassik, Lacramioara Bintu.
      Human gene expression is regulated by more than 2,000 transcription factors and chromatin regulators1,2. Effector domains within these proteins can activate or repress transcription. However, for many of these regulators we do not know what type of effector domains they contain, their location in the protein, their activation and repression strengths, and the sequences that are necessary for their functions. Here, we systematically measure the effector activity of more than 100,000 protein fragments tiling across most chromatin regulators and transcription factors in human cells (2,047 proteins). By testing the effect they have when recruited at reporter genes, we annotate 374 activation domains and 715 repression domains, roughly 80% of which are new and have not been previously annotated3-5. Rational mutagenesis and deletion scans across all the effector domains reveal aromatic and/or leucine residues interspersed with acidic, proline, serine and/or glutamine residues are necessary for activation domain activity. Furthermore, most repression domain sequences contain sites for small ubiquitin-like modifier (SUMO)ylation, short interaction motifs for recruiting corepressors or are structured binding domains for recruiting other repressive proteins. We discover bifunctional domains that can both activate and repress, some of which dynamically split a cell population into high- and low-expression subpopulations. Our systematic annotation and characterization of effector domains provide a rich resource for understanding the function of human transcription factors and chromatin regulators, engineering compact tools for controlling gene expression and refining predictive models of effector domain function.
    DOI:  https://doi.org/10.1038/s41586-023-05906-y
  29. Handb Exp Pharmacol. 2023 Apr 06.
    RNA Delivery to Mitochondria.
    Yuma Yamada, Hideyoshi Harashima.
      The approval of mRNA-containing lipid nanoparticles (LNPs) for use in a vaccine against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the clinical utility of RNA-loaded nanocapsules has stimulated a rapid acceleration in research in this area. The development of mRNA-containing LNP vaccines has been rapid, not only because of regulatory adjustments, but also to the advances made in nucleic acid delivery as the result of efforts by many basic researchers. RNA functions, not only in the nucleus and cytoplasm, but also in mitochondria, which have their own genomic apparatus. Mitochondrial diseases caused by mutations or defects in the mitochondrial genome, mitochondrial DNA (mtDNA) are intractable and are mainly treated symptomatically, but gene therapy as a fundamental treatment is expected to soon be a reality. To realize this therapy, a drug delivery system (DDS) that delivers nucleic acids including RNA to mitochondria is required, but efforts in this area have been limited compared to research targeting the nucleus and cytoplasm. This contribution provides an overview of mitochondria-targeted gene therapy strategies and discusses studies that have attempted to validate mitochondria-targeted RNA delivery therapies. We also present the results of 'RNA delivery to mitochondria' based on the use of our mitochondria-targeted DDS (MITO-Porter) that was developed in our laboratory.
    Keywords:  Gene therapy; MITO-Porter; Mitochondria; Mitochondrial drug delivery; RNA delivery; RNA knockdown
    DOI:  https://doi.org/10.1007/164_2023_650
  30. NPJ Aging. 2023 Apr 03. 9(1): 7
    Oral supplementation of nicotinamide riboside alters intestinal microbial composition in rats and mice, but not humans.
    A Augusto Peluso, Agnete T Lundgaard, Parizad Babaei, Felippe Mousovich-Neto, Andréa L Rocha, Mads V Damgaard, Emilie G Bak, Thiyagarajan Gnanasekaran, Ole L Dollerup, Samuel A J Trammell, Thomas S Nielsen, Timo Kern, Caroline B Abild, Karolina Sulek, Tao Ma, Zach Gerhart-Hines, Matthew P Gillum, Manimozhiyan Arumugam, Cathrine Ørskov, Douglas McCloskey, Niels Jessen, Markus J Herrgård, Marcelo A S Mori, Jonas T Treebak.
      The gut microbiota impacts systemic levels of multiple metabolites including NAD+ precursors through diverse pathways. Nicotinamide riboside (NR) is an NAD+ precursor capable of regulating mammalian cellular metabolism. Some bacterial families express the NR-specific transporter, PnuC. We hypothesized that dietary NR supplementation would modify the gut microbiota across intestinal sections. We determined the effects of 12 weeks of NR supplementation on the microbiota composition of intestinal segments of high-fat diet-fed (HFD) rats. We also explored the effects of 12 weeks of NR supplementation on the gut microbiota in humans and mice. In rats, NR reduced fat mass and tended to decrease body weight. Interestingly, NR increased fat and energy absorption but only in HFD-fed rats. Moreover, 16S rRNA gene sequencing analysis of intestinal and fecal samples revealed an increased abundance of species within Erysipelotrichaceae and Ruminococcaceae families in response to NR. PnuC-positive bacterial strains within these families showed an increased growth rate when supplemented with NR. The abundance of species within the Lachnospiraceae family decreased in response to HFD irrespective of NR. Alpha and beta diversity and bacterial composition of the human fecal microbiota were unaltered by NR, but in mice, the fecal abundance of species within Lachnospiraceae increased while abundances of Parasutterella and Bacteroides dorei species decreased in response to NR. In conclusion, oral NR altered the gut microbiota in rats and mice, but not in humans. In addition, NR attenuated body fat mass gain in rats, and increased fat and energy absorption in the HFD context.
    DOI:  https://doi.org/10.1038/s41514-023-00106-4
  31. Nat Rev Cancer. 2023 Apr 03.
    Mapping out mitochondria.
    Anna Dart.
      
    DOI:  https://doi.org/10.1038/s41568-023-00572-8
  32. Am J Med Genet A. 2023 May;191(5): 1141-1142
    Metabolomics as a Diagnostic Tool.
      
    DOI:  https://doi.org/10.1002/ajmg.a.62806
  33. Nature. 2023 Apr 05.
    mRNA decoding in human is kinetically and structurally distinct from bacteria.
    Mikael Holm, S Kundhavai Natchiar, Emily J Rundlet, Alexander G Myasnikov, Zoe L Watson, Roger B Altman, Hao-Yuan Wang, Jack Taunton, Scott C Blanchard.
      In all species, ribosomes synthesize proteins by faithfully decoding messenger RNA (mRNA) nucleotide sequences using aminoacyl-tRNA substrates. Current knowledge of the decoding mechanism derives principally from studies on bacterial systems1. Although key features are conserved across evolution2, eukaryotes achieve higher-fidelity mRNA decoding than bacteria3. In human, changes in decoding fidelity are linked to ageing and disease and represent a potential point of therapeutic intervention in both viral and cancer treatment4-6. Here we combine single-molecule imaging and cryogenic electron microscopy methods to examine the molecular basis of human ribosome fidelity to reveal that the decoding mechanism is both kinetically and structurally distinct from that of bacteria. Although decoding is globally analogous in both species, the reaction coordinate of aminoacyl-tRNA movement is altered on the human ribosome and the process is an order of magnitude slower. These distinctions arise from eukaryote-specific structural elements in the human ribosome and in the elongation factor eukaryotic elongation factor 1A (eEF1A) that together coordinate faithful tRNA incorporation at each mRNA codon. The distinct nature and timing of conformational changes within the ribosome and eEF1A rationalize how increased decoding fidelity is achieved and potentially regulated in eukaryotic species.
    DOI:  https://doi.org/10.1038/s41586-023-05908-w
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