bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2023–01–01
23 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Editors' Note: Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis.
  2. Reader Response: Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis.
  3. Author Response: Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis.
  4. Low disease risk and penetrance in Leber hereditary optic neuropathy.
  5. Synthetic mRNA rescues very long-chain acyl-CoA dehydrogenase deficiency in patient fibroblasts and a murine model.
  6. DNA-protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM).
  7. Mitochondria-localized lncRNA HITT inhibits fusion by attenuating formation of mitofusin-2 homo- or heterotypic complexes.
  8. Molecular mechanism of substrate recognition by folate transporter SLC19A1.
  9. Incompatibilities between common mtDNA variants in human disease.
  10. Mitochondrial genome recovery by ATFS-1 is essential for development after starvation.
  11. High-frequency and functional mitochondrial DNA mutations at the single-cell level.
  12. Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?
  13. Case report: A novel variant in SLC25A46 causing sensorimotor polyneuropathy and optic atrophy.
  14. UCP2-dependent redox sensing in POMC neurons regulates feeding.
  15. Mitochondria and peroxisomes: partners in autophagy.
  16. Small molecule-mediated rapid maturation of human induced pluripotent stem cell-derived cardiomyocytes.
  17. Detecting mitochondrial mutations associated with aminoglycoside ototoxicity by noninvasive prenatal testing.
  18. The membrane domain of respiratory complex I accumulates during muscle aging in Drosophila melanogaster.
  19. Age-associated alterations of brain mitochondria energetics.
  20. Simultaneous profiling of histone modifications and DNA methylation via nanopore sequencing.
  21. Editorial: The fiber profile of skeletal muscles as a fingerprint of muscle quality.
  22. Integrated View of Baseline Protein Expression in Human Tissues.
  23. Mitochondria directly sense osmotic stress to trigger rapid metabolic remodeling via regulation of pyruvate dehydrogenase (PDH) phosphorylation.
  1. Neurology. 2023 01 03. 100(1): 49
    Editors' Note: Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis.
    James E Siegler, Steven Galetta.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000201675
  2. Neurology. 2023 01 03. 100(1): 49-50
    Reader Response: Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis.
    Katherine Schon, Patrick Chinnery.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000201676
  3. Neurology. 2023 01 03. 100(1): 50
    Author Response: Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis.
    Ryan L Davis, Kishore R Kumar, Eloise C Watson, Carolyn M Sue.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000201677
  4. Am J Hum Genet. 2022 Dec 21. pii: S0002-9297(22)00504-3. [Epub ahead of print]
    Low disease risk and penetrance in Leber hereditary optic neuropathy.
    Eloise C Watson, Ryan L Davis, Shyamsundar Ravishankar, Joseph Copty, Sarah Kummerfeld, Carolyn M Sue.
      The risk of Leber hereditary optic neuropathy (LHON) has largely been extrapolated from disease cohorts, which underestimate the population prevalence of pathogenic primary LHON variants as a result of incomplete disease penetrance. Understanding the true population prevalence of primary LHON variants, alongside the rate of clinical disease, provides a better understanding of disease risk and variant penetrance. We identified pathogenic primary LHON variants in whole-genome sequencing data of a well-characterized population-based control cohort and found that the prevalence is far greater than previously estimated, as it occurs in approximately 1 in 800 individuals. Accordingly, we were able to more accurately estimate population risk and disease penetrance in LHON variant carriers, validating our findings by using other large control datasets. These findings will inform accurate counseling in relation to the risk of vision loss in LHON variant carriers and disease manifestation in their family. This Matters Arising paper is in response to Lopez Sanchez et al. (2021), published in The American Journal of Human Genetics. See also the response by Mackey et al. (2022), published in this issue.
    Keywords:  LHON; Leber hereditary optic neuropathy; mitochondrial disease; penetrance; prevalence; risk; vision los
    DOI:  https://doi.org/10.1016/j.ajhg.2022.11.013
  5. Mol Genet Metab. 2022 Dec 23. pii: S1096-7192(22)00460-7. [Epub ahead of print]138(1): 106982
    Synthetic mRNA rescues very long-chain acyl-CoA dehydrogenase deficiency in patient fibroblasts and a murine model.
    Xue-Jun Zhao, Ai-Walid Mohsen, Stephanie Mihalik, Keaton Solo, Ermal Aliu, Huifang Shi, Shakuntala Basu, Catherine Kochersperger, Clinton Van't Land, Anuradha Karunanidhi, Kimberly A Coughlan, Summar Siddiqui, Lisa M Rice, Shawn Hillier, Eleonora Guadagnin, Paloma H Giangrande, Paolo G V Martini, Jerry Vockley.
      Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inborn error of long chain fatty acid β-oxidation (FAO) with limited treatment options. Patients present with heterogeneous clinical phenotypes affecting predominantly heart, liver, and skeletal muscle. While VLCAD deficiency is a systemic disease, restoration of liver FAO has the potential to improve symptoms more broadly due to increased total body ATP production and reduced accumulation of potentially toxic metabolites. We explored the use of synthetic human VLCAD (hVLCAD) mRNA and lipid nanoparticle encapsulated hVLCAD mRNA (LNP-VLCAD) to generate functional VLCAD enzyme in patient fibroblasts derived from VLCAD deficient patients, mouse embryonic fibroblasts, hepatocytes isolated from VLCAD knockout (Acadvl-/-) mice, and Acadvl-/- mice to reverse the metabolic effects of the deficiency. Transfection of all cell types with hVLCAD mRNA resulted in high level expression of protein that localized to mitochondria with increased enzyme activity. Intravenous administration of LNP-VLCAD to Acadvl-/- mice produced a significant amount of VLCAD protein in liver, which declined over a week. Treated Acadvl-/- mice showed reduced hepatic steatosis, were more resistant to cold stress, and accumulated less toxic metabolites in blood than untreated animals. Results from this study support the potential for hVLCAD mRNA for treatment of VLCAD deficiency.
    Keywords:  Acadvl(-/-) mouse; Fatty acid β-oxidation; Fibroblasts; Synthetic mRNA; Very long-chain acyl-CoA dehydrogenase deficiency
    DOI:  https://doi.org/10.1016/j.ymgme.2022.106982
  6. Nucleic Acids Res. 2022 Dec 30. pii: gkac1214. [Epub ahead of print]
    DNA-protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM).
    Wenyan Xu, Jin Tang, Linlin Zhao.
      In higher eukaryotic cells, mitochondria are essential organelles for energy production, metabolism, and signaling. Mitochondrial DNA (mtDNA) encodes 13 protein subunits for oxidative phosphorylation and a set of tRNAs and rRNAs. mtDNA damage, sourced from endogenous chemicals and environmental factors, contributes to mitochondrial genomic instability, which has been associated with various mitochondrial diseases. DNA-protein cross-links (DPCs) are deleterious DNA lesions that threaten genomic integrity. Although much has been learned about the formation and repair of DPCs in the nucleus, little is known about DPCs in mitochondria. Here, we present in vitro and in cellulo data to demonstrate the formation of DPCs between a prevalent abasic (AP) DNA lesion and a DNA-packaging protein, mitochondrial transcription factor A (TFAM). TFAM cleaves AP-DNA and forms DPCs and single-strand breaks (SSB). Lys residues of TFAM are critical for the formation of TFAM-DPC and a reactive 3'-phospho-α,β-unsaturated aldehyde (3'pUA) residue on SSB. The 3'pUA residue reacts with two Cys of TFAM and contributes to the stable TFAM-DPC formation. Glutathione reacts with 3'pUA and competes with TFAM-DPC formation, corroborating our cellular experiments showing the accumulation of TFAM-DPCs under limiting glutathione. Our data point to the involvement of TFAM in AP-DNA turnover and fill a knowledge gap regarding the protein factors in processing damaged mtDNA.
    DOI:  https://doi.org/10.1093/nar/gkac1214
  7. J Biol Chem. 2022 Dec 22. pii: S0021-9258(22)01268-6. [Epub ahead of print] 102825
    Mitochondria-localized lncRNA HITT inhibits fusion by attenuating formation of mitofusin-2 homo- or heterotypic complexes.
    Xingwen Wang, Yi Zhang, Qingyu Lin, Kunming Zhao, Dantong Zhu, Ying Hu.
      Long non-coding RNAs (lncRNAs) are emerging as essential players in multiple biological processes. Mitochondrial dynamics, comprising the continuous cycle of fission and fusion, are required for healthy mitochondria that function properly. Despite long-term recognition of its significance in cell-fate control, the mechanism underlying mitochondrial fusion is not completely understood, particularly regarding the involvement of lncRNAs. Here, we show that the lncRNA HITT (HIF-1α inhibitor at translation level), can specifically localize in mitochondria. Cells expressing higher levels of HITT contain fragmented mitochondria. Conversely, we show that HITT knockdown cells have more tubular mitochondria than is present in control cells. Mechanistically, we demonstrate HITT directly binds mitofusin-2 (MFN2), a core component that mediates mitochondrial outer membrane fusion, by the in vitro RNA pull-down and UV-cross-linking RNA-IP (CLIP) assays. In doing so, we found HITT disturbs MFN2 homo- or heterotypic complex formation, attenuating mitochondrial fusion. Under stress conditions, such as ultraviolet radiation, we in addition show HITT stability increases as a consequence of MiR-205 downregulation, inhibiting MFN2-mediated fusion and leading to apoptosis. Overall, our data provide significant insights into the roles of organelle (mitochondria)-specific resident lncRNAs in regulating mitochondrial fusion, and also reveal how such a mechanism controls cellular sensitivity to UV radiation-induced apoptosis.
    Keywords:  LINC00637; MFN2; apoptosis; mitochondrial dynamics; mitochondrial fusion
    DOI:  https://doi.org/10.1016/j.jbc.2022.102825
  8. Cell Discov. 2022 Dec 28. 8(1): 141
    Molecular mechanism of substrate recognition by folate transporter SLC19A1.
    Yu Dang, Dong Zhou, Xiaojuan Du, Hongtu Zhao, Chia-Hsueh Lee, Jing Yang, Yijie Wang, Changdong Qin, Zhenxi Guo, Zhe Zhang.
      Folate (vitamin B9) is the coenzyme involved in one-carbon transfer biochemical reactions essential for cell survival and proliferation, with its inadequacy causing developmental defects or severe diseases. Notably, mammalian cells lack the ability to de novo synthesize folate but instead rely on its intake from extracellular sources via specific transporters or receptors, among which SLC19A1 is the ubiquitously expressed one in tissues. However, the mechanism of substrate recognition by SLC19A1 remains unclear. Here we report the cryo-EM structures of human SLC19A1 and its complex with 5-methyltetrahydrofolate at 3.5-3.6 Å resolution and elucidate the critical residues for substrate recognition. In particular, we reveal that two variant residues among SLC19 subfamily members designate the specificity for folate. Moreover, we identify intracellular thiamine pyrophosphate as the favorite coupled substrate for folate transport by SLC19A1. Together, this work establishes the molecular basis of substrate recognition by this central folate transporter.
    DOI:  https://doi.org/10.1038/s41421-022-00508-w
  9. Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2217452119
    Incompatibilities between common mtDNA variants in human disease.
    Weilin Pu, Zhenglong Gu.
      
    DOI:  https://doi.org/10.1073/pnas.2217452119
  10. Cell Rep. 2022 Dec 27. pii: S2211-1247(22)01771-5. [Epub ahead of print]41(13): 111875
    Mitochondrial genome recovery by ATFS-1 is essential for development after starvation.
    Nandhitha Uma Naresh, Sookyung Kim, Tomer Shpilka, Qiyuan Yang, Yunguang Du, Cole M Haynes.
      Nutrient availability regulates the C. elegans life cycle as well as mitochondrial physiology. Food deprivation significantly reduces mitochondrial genome (mtDNA) numbers and leads to aging-related phenotypes. Here we show that the bZIP (basic leucine zipper) protein ATFS-1, a mediator of the mitochondrial unfolded protein response (UPRmt), is required to promote growth and establish a functional germline after prolonged starvation. We find that recovery of mtDNA copy numbers and development after starvation requires mitochondrion-localized ATFS-1 but not its nuclear transcription activity. We also find that the insulin-like receptor DAF-2 functions upstream of ATFS-1 to modulate mtDNA content. We show that reducing DAF-2 activity represses ATFS-1 nuclear function while causing an increase in mtDNA content, partly mediated by mitochondrion-localized ATFS-1. Our data indicate the importance of the UPRmt in recovering mitochondrial mass and suggest that atfs-1-dependent mtDNA replication precedes mitochondrial network expansion after starvation.
    Keywords:  ATFS-1; C. elegans; CP: Metabolism; CP: Molecular biology; DAF-2; UPR; UPRmt; insulin receptor; mitochondria; mtDNA; starvation; stress response
    DOI:  https://doi.org/10.1016/j.celrep.2022.111875
  11. Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2201518120
    High-frequency and functional mitochondrial DNA mutations at the single-cell level.
    Xiaoxian Guo, Weilin Xu, Weiping Zhang, Cuiping Pan, Anna E Thalacker-Mercer, Hongxiang Zheng, Zhenglong Gu.
      Decline in mitochondrial function underlies aging and age-related diseases, but the role of mitochondrial DNA (mtDNA) mutations in these processes remains elusive. To investigate patterns of mtDNA mutations, it is particularly important to quantify mtDNA mutations and their associated pathogenic effects at the single-cell level. However, existing single-cell mtDNA sequencing approaches remain inefficient due to high cost and low mtDNA on-target rates. In this study, we developed a cost-effective mtDNA targeted-sequencing protocol called single-cell sequencing by targeted amplification of multiplex probes (scSTAMP) and experimentally validated its reliability. We then applied our method to assess single-cell mtDNA mutations in 768 B lymphocytes and 768 monocytes from a 76-y-old female. Across 632 B lymphocyte and 617 monocytes with medium mtDNA coverage over >100×, our results indicated that over 50% of cells carried at least one mtDNA mutation with variant allele frequencies (VAFs) over 20%, and that cells carried an average of 0.658 and 0.712 such mutation for B lymphocytes and monocytes, respectively. Surprisingly, more than 20% of the observed mutations had VAFs of over 90% in either cell population. In addition, over 60% of the mutations were in protein-coding genes, of which over 70% were nonsynonymous, and more than 50% of the nonsynonymous mutations were predicted to be highly pathogenic. Interestingly, about 80% of the observed mutations were singletons in the respective cell populations. Our results revealed mtDNA mutations with functional significance might be prevalent at advanced age, calling further investigation on age-related mtDNA mutation dynamics at the single-cell level.
    Keywords:  aging; mitochondrial DNA; single cell
    DOI:  https://doi.org/10.1073/pnas.2201518120
  12. Am J Hum Genet. 2022 Dec 20. pii: S0002-9297(22)00505-5. [Epub ahead of print]
    Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?
    David A Mackey, Jue-Sheng Ong, Stuart MacGregor, David C Whiteman, Jamie E Craig, M Isabel G Lopez Sanchez, Lisa S Kearns, Sandra E Staffieri, Linda Clarke, Myra B McGuinness, Wafaa Meteoukki, Sona Samuel, Jonathan B Ruddle, Celia Chen, Clare L Fraser, John Harrison, Neil Howell, Alex W Hewitt.
      Pedigree analysis showed that a large proportion of Leber hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk variant never lose vision. Mitochondrial haplotype appears to be a major factor influencing the risk of vision loss from LHON. Mitochondrial variants, including m.14484T>C and m.11778G>A, have been added to gene arrays, and thus many patients and research participants are tested for LHON mutations. Analysis of the UK Biobank and Australian cohort studies found more than 1 in 1,000 people in the general population carry either the m.14484T>C or the m.11778G>A LHON variant. None of the subset of carriers examined had visual acuity at 20/200 or worse, suggesting a very low penetrance of LHON. Haplogroup analysis of m.14484T>C carriers showed a high rate of haplogroup U subclades, previously shown to have low penetrance in pedigrees. Penetrance calculations of the general population are lower than pedigree calculations, most likely because of modifier genetic factors. This Matters Arising Response paper addresses the Watson et al. (2022) Matters Arising paper, published concurrently in The American Journal of Human Genetics.
    Keywords:  LHON; UK Biobank; haplogroup; m.11778G>A; m.14484T>C; mitochondria; mtDNA; myocilin; prevalence
    DOI:  https://doi.org/10.1016/j.ajhg.2022.11.014
  13. Front Neurol. 2022 ;13 1066040
    Case report: A novel variant in SLC25A46 causing sensorimotor polyneuropathy and optic atrophy.
    Louise Sloth Kodal, Sophia Hammer-Hansen, Sonja Holm-Yildiz, Karen Grønskov, Helena Gásdal Karstensen, Tina Dysgaard.
      SLC25A46 is a mitochondrial protein involved in mitochondrial dynamics. Recently, bi-allelic variants have been identified as a pathogenic cause in a spectrum of neurological syndromes. We report a novel homozygous SLC25A46 variant in two siblings, originating from Iraq. Both presented with optic atrophy and varying neurological symptoms. The neurological examination and nerve conduction studies were consistent with sensorimotor polyneuropathy, one having mild polyneuropathy and the other pronounced polyneuropathy. The cases illustrate the disease spectrum and provide substantial information to the knowledge of polyneuropathy caused by SLC25A46 variants. It further highlights the diagnostic potentials of whole exome sequencing which can improve future understanding of disease mechanisms.
    Keywords:  case report; hereditary neuropathy; optic atrophy; polyneuropathy; whole exome sequencing
    DOI:  https://doi.org/10.3389/fneur.2022.1066040
  14. Cell Rep. 2022 Dec 27. pii: S2211-1247(22)01793-4. [Epub ahead of print]41(13): 111894
    UCP2-dependent redox sensing in POMC neurons regulates feeding.
    Nal Ae Yoon, Sungho Jin, Jung Dae Kim, Zhong Wu Liu, Qiushi Sun, Rebecca Cardone, Richard Kibbey, Sabrina Diano.
      Paradoxically, glucose, the primary driver of satiety, activates a small population of anorexigenic pro-opiomelanocortin (POMC) neurons. Here, we show that lactate levels in the circulation and in the cerebrospinal fluid are elevated in the fed state and the addition of lactate to glucose activates the majority of POMC neurons while increasing cytosolic NADH generation, mitochondrial respiration, and extracellular pyruvate levels. Inhibition of lactate dehydrogenases diminishes mitochondrial respiration, NADH production, and POMC neuronal activity. However, inhibition of the mitochondrial pyruvate carrier has no effect. POMC-specific downregulation of Ucp2 (Ucp2PomcKO), a molecule regulated by fatty acid metabolism and shown to play a role as transporter in the malate-aspartate shuttle, abolishes lactate- and glucose-sensing of POMC neurons. Ucp2PomcKO mice have impaired glucose metabolism and are prone to obesity on a high-fat diet. Altogether, our data show that lactate through redox signaling and blocking mitochondrial glucose utilization activates POMC neurons to regulate feeding and glucose metabolism.
    Keywords:  CP: Metabolism; CP: Neuroscience; NADH; UCP2; feeding behavior; glucose; hypothalamus; lactate; lipid utilization; mitochondria; pro-opiomelanocortin neurons; redox signaling
    DOI:  https://doi.org/10.1016/j.celrep.2022.111894
  15. Autophagy. 2022 Dec 26. 1-2
    Mitochondria and peroxisomes: partners in autophagy.
    Léa P Wilhelm, Ian G Ganley.
      Mitochondria, often called "the powerhouse" of the cell due to their role as the main energy supplier, regulate numerous complex processes including intracellular calcium homeostasis, reactive oxygen species (ROS) production, regulation of immune responses, and apoptosis. So, mitochondria are a fundamental metabolic hub that also control cell survival and cell death. However, they are not unique in all these functions. Indeed, peroxisomes are small cytoplasmic organelles that also ensure metabolic functions such as fatty acid oxidation and ROS production. This common relationship also extends beyond function as peroxisomes themselves can form from mitochondrial-derived precursors. Given this interconnection between mitochondria and peroxisomes involving biogenesis and function, in our recent work we determined if their turnover was also linked.
    Keywords:  Autophagy; BNIP3L; NIX; mitophagy; pexophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2155368
  16. Stem Cell Res Ther. 2022 Dec 27. 13(1): 531
    Small molecule-mediated rapid maturation of human induced pluripotent stem cell-derived cardiomyocytes.
    Nino Chirico, Elise L Kessler, Renée G C Maas, Juntao Fang, Jiabin Qin, Inge Dokter, Mark Daniels, Tomo Šarić, Klaus Neef, Jan-Willem Buikema, Zhiyong Lei, Pieter A Doevendans, Joost P G Sluijter, Alain van Mil.
       BACKGROUND: Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) do not display all hallmarks of mature primary cardiomyocytes, especially the ability to use fatty acids (FA) as an energy source, containing high mitochondrial mass, presenting binucleation and increased DNA content per nuclei (polyploidism), and synchronized electrical conduction. This immaturity represents a bottleneck to their application in (1) disease modelling-as most cardiac (genetic) diseases have a middle-age onset-and (2) clinically relevant models, where integration and functional coupling are key. So far, several methods have been reported to enhance iPSC-CM maturation; however, these protocols are laborious, costly, and not easily scalable. Therefore, we developed a simple, low-cost, and rapid protocol to promote cardiomyocyte maturation using two small molecule activators of the peroxisome proliferator-activated receptor β/δ and gamma coactivator 1-alpha (PPAR/PGC-1α) pathway: asiatic acid (AA) and GW501516 (GW). METHODS AND RESULTS: Monolayers of iPSC-CMs were incubated with AA or GW every other day for ten days resulting in increased expression of FA metabolism-related genes and markers for mitochondrial activity. AA-treated iPSC-CMs responsiveness to the mitochondrial respiratory chain inhibitors increased and exhibited higher flexibility in substrate utilization. Additionally, structural maturity improved after treatment as demonstrated by an increase in mRNA expression of sarcomeric-related genes and higher nuclear polyploidy in AA-treated samples. Furthermore, treatment led to increased ion channel gene expression and protein levels.
    CONCLUSIONS: Collectively, we developed a fast, easy, and economical method to induce iPSC-CMs maturation via PPAR/PGC-1α activation. Treatment with AA or GW led to increased metabolic, structural, functional, and electrophysiological maturation, evaluated using a multiparametric quality assessment.
    Keywords:  Asiatic acid; GW501516; Human induced pluripotent stem cell-derived cardiomyocyte; Maturation; PGC-1α; PPAR
    DOI:  https://doi.org/10.1186/s13287-022-03209-z
  17. J Clin Lab Anal. 2022 Dec 29. e24827
    Detecting mitochondrial mutations associated with aminoglycoside ototoxicity by noninvasive prenatal testing.
    Quanfei Huang, Yanhui Liu, Wei Lei, Jiajie Liang, Yang Wang, Minhua Zheng, Xiaoyan Huang, Yuanru Liu, Kaisheng Huang, Min Huang.
       OBJECTIVES: Numerous diseases and disorders are associated with mitochondrial DNA (mtDNA) mutations, among which m.1555A > G and m.1494C > T mutations in the 12 S ribosomal RNA gene contribute to aminoglycoside-induced and nonsyndromic hearing loss worldwide.
    METHODS: A total of 76,842 qualified non-invasive prenatal (NIPT) samples were subjected to mtDNA mutation and haplogroup analysis.
    RESULTS: We detected 181 m.1555A > G and m.1494C > T mutations, 151 of which were subsequently sequenced for full-length mitochondrial genome verification. The positive predictive values for the m.1555A > G and m.1494C > T mutations were 90.78% and 90.00%, respectively, a performance comparable to that attained with newborn hearing screening. Furthermore, mitochondrial haplogroup analysis revealed that the 12 S rRNA 1555A > G mutation was enriched in sub-haplotype D5[p = 0, OR = 4.6706(2.81-7.78)].
    CONCLUSIONS: Our findings indicate that the non-invasive prenatal testing of cell-free DNA obtained from maternal plasma can successfully detect m.1555A > G and m.1494C > T mutations.
    Keywords:  PPV; mitochondrial DNA (mtDNA); newborn hearing screening (NBHS); noninvasive prenatal testing (NIPT); secondary finding
    DOI:  https://doi.org/10.1002/jcla.24827
  18. Sci Rep. 2022 Dec 27. 12(1): 22433
    The membrane domain of respiratory complex I accumulates during muscle aging in Drosophila melanogaster.
    Kaniz Fatima Binte Hossain, Anjaneyulu Murari, Bibhuti Mishra, Edward Owusu-Ansah.
      The boot-shaped respiratory complex I (CI) consists of a mitochondrial matrix and membrane domain organized into N-, Q- and P-modules. The N-module is the most distal part of the matrix domain, whereas the Q-module is situated between the N-module and the membrane domain. The proton-pumping P-module is situated in the membrane domain. We explored the effect of aging on the disintegration of CI and its constituent subcomplexes and modules in Drosophila flight muscles. We find that the fully-assembled complex remains largely intact in aged flies. And while the effect of aging on the stability of many Q- and N-module subunits in subcomplexes was stochastic, NDUFS3 was consistently down-regulated in subcomplexes with age. This was associated with an accumulation of many P-module subunits in subcomplexes. The potential significance of these studies is that genetic manipulations aimed at boosting, perhaps, a few CI subunits may suffice to restore the whole CI biosynthesis pathway during muscle aging.
    DOI:  https://doi.org/10.1038/s41598-022-26414-5
  19. Biochem Biophys Res Commun. 2022 Dec 23. pii: S0006-291X(22)01741-7. [Epub ahead of print]643 1-7
    Age-associated alterations of brain mitochondria energetics.
    Timur Gainutdinov, Zemfira Gizatullina, Grazyna Debska-Vielhaber, Stefan Vielhaber, Robert Feldmann, Zulfiya Orynbayeva, Frank Norbert Gellerich.
      The study aimed to explore the role of age-associated elevated cytosolic Ca2+ in changes of brain mitochondria energetic processes. Two groups of rats, young adults (4 months) and advanced old (24 months), were evaluated for potential alterations of mitochondrial parameters, the oxidative phosphorylation (OxPhos), membrane potential, calcium retention capacity, activity of glutamate/aspartate carrier (aralar), and ROS formation. We demonstrated that the brain mitochondria of older animals have a lower resistance to Ca2+ stress with resulting consequences. The suppressed complex I OxPhos and decreased membrane potential were accompanied by reduction of the Ca2+ threshold required for induction of mPTP. The Ca2+ binding sites of mitochondrial aralar mediated a lower activity of old brain mitochondria. The altered interaction between aralar and mPTP may underlie mitochondrial dysregulation leading to energetic depression during aging. At the advanced stages of aging, the declined metabolism is accompanied by the diminished oxidative background.
    Keywords:  Aging; Aralar; Brain mitochondria; Ca(2+); OxPhos; ROS
    DOI:  https://doi.org/10.1016/j.bbrc.2022.12.070
  20. Nat Commun. 2022 12 24. 13(1): 7939
    Simultaneous profiling of histone modifications and DNA methylation via nanopore sequencing.
    Xue Yue, Zhiyuan Xie, Moran Li, Kai Wang, Xiaojing Li, Xiaoqing Zhang, Jian Yan, Yimeng Yin.
      The interplay between histone modifications and DNA methylation drives the establishment and maintenance of the cellular epigenomic landscape, but it remains challenging to investigate the complex relationship between these epigenetic marks across the genome. Here we describe a nanopore-sequencing-based-method, nanoHiMe-seq, for interrogating the genome-wide localization of histone modifications and DNA methylation from single DNA molecules. nanoHiMe-seq leverages a nonspecific methyltransferase to exogenously label adenine bases proximal to antibody-targeted modified nucleosomes in situ. The labelled adenines and the endogenous methylated CpG sites are simultaneously detected on individual nanopore reads using a hidden Markov model, which is implemented in the nanoHiMe software package. We demonstrate the utility, robustness and sensitivity of nanoHiMe-seq by jointly profiling DNA methylation and histone modifications at low coverage depths, concurrently determining phased patterns of DNA methylation and histone modifications, and probing the intrinsic connectivity between these epigenetic marks across the genome.
    DOI:  https://doi.org/10.1038/s41467-022-35650-2
  21. Front Physiol. 2022 ;13 1105252
    Editorial: The fiber profile of skeletal muscles as a fingerprint of muscle quality.
    Emiliana Giacomello, Luana Toniolo.
      
    Keywords:  fiber profile; fiber size; metabolic activity; myosin heavy chain; oxidative capacity; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2022.1105252
  22. J Proteome Res. 2022 Dec 28.
    Integrated View of Baseline Protein Expression in Human Tissues.
    Ananth Prakash, David García-Seisdedos, Shengbo Wang, Deepti Jaiswal Kundu, Andrew Collins, Nancy George, Pablo Moreno, Irene Papatheodorou, Andrew R Jones, Juan Antonio Vizcaíno.
      The availability of proteomics datasets in the public domain, and in the PRIDE database, in particular, has increased dramatically in recent years. This unprecedented large-scale availability of data provides an opportunity for combined analyses of datasets to get organism-wide protein abundance data in a consistent manner. We have reanalyzed 24 public proteomics datasets from healthy human individuals to assess baseline protein abundance in 31 organs. We defined tissue as a distinct functional or structural region within an organ. Overall, the aggregated dataset contains 67 healthy tissues, corresponding to 3,119 mass spectrometry runs covering 498 samples from 489 individuals. We compared protein abundances between different organs and studied the distribution of proteins across these organs. We also compared the results with data generated in analogous studies. Additionally, we performed gene ontology and pathway-enrichment analyses to identify organ-specific enriched biological processes and pathways. As a key point, we have integrated the protein abundance results into the resource Expression Atlas, where they can be accessed and visualized either individually or together with gene expression data coming from transcriptomics datasets. We believe this is a good mechanism to make proteomics data more accessible for life scientists.
    Keywords:  human proteome; mass spectrometry; public data re-use; quantitative proteomics
    DOI:  https://doi.org/10.1021/acs.jproteome.2c00406
  23. J Biol Chem. 2022 Dec 26. pii: S0021-9258(22)01280-7. [Epub ahead of print] 102837
    Mitochondria directly sense osmotic stress to trigger rapid metabolic remodeling via regulation of pyruvate dehydrogenase (PDH) phosphorylation.
    Takeshi Ikizawa, Kazutaka Ikeda, Makoto Arita, Shojiro Kitajima, Tomoyoshi Soga, Hidenori Ichijo, Isao Naguro.
      A high-salt diet significantly impacts various diseases, including cancer and immune diseases. Recent studies suggest that the high-salt/hyperosmotic environment in the body may alter the chronic properties of cancer and immune cells in the disease context. However, little is known about the acute metabolic changes in hyperosmotic stress. Here, we found that hyperosmotic stress for a few minutes induces Warburg-like metabolic remodeling in HeLa and Raw264.7 cells and suppresses fatty acid oxidation. Regarding Warburg-like remodeling, we determined that the pyruvate dehydrogenase (PDH) phosphorylation status was altered bidirectionally (high in hyperosmolarity and low in hypoosmolarity) to osmotic stress in isolated mitochondria, suggesting that mitochondria themselves have an acute osmo-sensing mechanism. Additionally, we demonstrate that Warburg-like remodeling is required for HeLa cells to maintain ATP levels and survive under hyperosmotic conditions. Collectively, our findings suggest that cells exhibit acute metabolic remodeling under osmotic stress via the regulation of PDH phosphorylation by direct osmosensing within mitochondria.
    Keywords:  Acyl-carnitine; Metabolic remodeling; Mitochondria; Osmotic stress; Pyruvate dehydrogenase
    DOI:  https://doi.org/10.1016/j.jbc.2022.102837
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