bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2023–10–15
71 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes.
  2. Diversities in Leigh Syndrome Associated with MT-ATP6 Gene Variants.
  3. Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.
  4. CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature.
  5. COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.
  6. The First Reported Case of a Child with Two Different Rare Metabolic Disorders: Very Long-Chain Acyl-CoA Dehydrogenase Deficiency and Encephalomyopathic Mitochondrial DNA Depletion Syndrome 13.
  7. The functional significance of mitochondrial respiratory chain supercomplexes.
  8. Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis.
  9. PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.
  10. Hem25p is required for mitochondrial IPP transport in fungi.
  11. Exercise mitigates Age-related Metabolic Diseases by improving Mitochondrial Dysfunction.
  12. Homozygous MFN2 variants causing severe antenatal encephalopathy with clumped mitochondria.
  13. FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes.
  14. BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome.
  15. Drosophila Mpv17 forms an ion channel and regulates energy metabolism.
  16. Apoptotic stress causes mtDNA release during senescence and drives the SASP.
  17. Current management of primary mitochondrial disorders in EU countries: the European Reference Networks survey.
  18. Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.
  19. Extracellular release in the quality control of the mammalian mitochondria.
  20. The burden of mitochondrial disease with associated seizures: systematic literature reviews of health-related quality of life, utilities, costs and healthcare resource use data.
  21. Crosstalk between mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis.
  22. The roles of FGF21 and GDF15 in mediating the mitochondrial integrated stress response.
  23. Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism.
  24. Higher-order structural organization of the mitochondrial proteome charted by in situ cross-linking mass spectrometry.
  25. Role of Mitochondrial Dysfunction in Cellular Lipid Homeostasis and Disease.
  26. THE ROLE OF GENETICS IN DISEASE DIAGNOSIS AND TREATMENT MITOCHONDRIAL RESPIRATORY CHAIN DYSREGULATION IN GENOMIC MEDICINE.
  27. Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.
  28. Mitochondrial Fragmentation Promotes Inflammation Resolution Responses in Macrophages via Histone Lactylation.
  29. Glial-derived mitochondrial signals affect neuronal proteostasis and aging.
  30. The Emerging Role of the Mitochondrial Respiratory Chain in Skeletal Aging.
  31. ApoE enhances mitochondrial metabolism via microRNA-142a/146a-regulated circuits that suppress hematopoiesis and inflammation in hyperlipidemia.
  32. The therapeutic potential of targeting ferroptosis in the treatment of mitochondrial cardiomyopathies and heart failure.
  33. MOF moves into mitochondria.
  34. WTAP boosts lipid oxidation and induces diabetic cardiac fibrosis by enhancing AR methylation.
  35. GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle.
  36. Brain mitochondria in behavior: more than a powerhouse.
  37. Vanadium Pentoxide Exposure Causes Strain-Dependent Changes in Mitochondrial DNA Heteroplasmy, Copy Number, and Lesions, but Not Nuclear DNA Lesions.
  38. GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes.
  39. Adrenocortical function in patients with Single Large Scale Mitochondrial DNA Deletions: a retrospective single centre cohort study.
  40. Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration.
  41. The misregulation of mitochondria-associated genes caused by GAGA-factor lack promotes autophagic germ cell death in Drosophila testes.
  42. Constructing and interpreting a large-scale variant effect map for an ultrarare disease gene: Comprehensive prediction of the functional impact of PSAT1 genotypes.
  43. Forward genetic screens identify mechanisms of resistance to small molecule lactate dehydrogenase inhibitors.
  44. Next-generation sequencing improves precision medicine in hearing loss.
  45. Carnitine acetyltransferase deficiency mediates mitochondrial dysfunction-induced cellular senescence in dermal fibroblasts.
  46. Predicting variant pathogenicity with AlphaMissense.
  47. Simulation of undiagnosed patients with novel genetic conditions.
  48. Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition.
  49. Reactive nitrogen species inhibit branched chain alpha-ketoacid dehydrogenase complex and impact muscle cell metabolism.
  50. Mitochondrial Dysfunction and Decreased Cytochrome c in Cell and Animal Models of Machado-Joseph Disease.
  51. A comparative atlas of single-cell chromatin accessibility in the human brain.
  52. Structures illustrate step-by-step mitochondrial transcription initiation.
  53. The multifaceted role of mitochondria in HSC fate decisions: energy and beyond.
  54. Facilitating the Molecular Diagnosis of Rare Genetic Disorders Through Facial Phenotypic Scores.
  55. Monitoring protein proximity with fluorogens.
  56. A feasible molecular diagnostic strategy for rare genetic disorders within resource-constrained environments.
  57. Allogeneic mitochondrial transplantation ameliorates cardiac dysfunction due to doxorubicin: An in vivo study.
  58. Intellectual disability syndrome associated with a homozygous founder variant in SGSM3 in Ashkenazi Jews.
  59. Mitochondrial Respiration and Exercise Performance in Patients With Heart Failure With Preserved Ejection Fraction.
  60. Low-dose atorvastatin protects skeletal muscle mitochondria in high-fat diet-fed mice with mitochondrial autophagy inhibition and fusion enhancement.
  61. Mitochondrial dysfunction promotes microbial composition that negatively impacts on ulcerative colitis development and progression.
  62. Phenotype and natural history of mitochondrial membrane protein-associated neurodegeneration.
  63. Succinate dehydrogenase is essential for epigenetic and metabolic homeostasis in hearts.
  64. Mitochondrial regulator PGC-1a in neuronal metabolism and brain aging.
  65. N6-Methyladenine Progressively Accumulates in Mitochondrial DNA during Aging.
  66. Neuroprotective Bioorthogonal Catalysis in Mitochondria using Protein-Integrated Hydrogen-Bonded Organic Frameworks.
  67. Uncouplers of mitochondrial oxidation in non-alcoholic fatty liver disease.
  68. Leber hereditary optic neuropathy presenting as bilateral visual loss and white matter disease.
  69. Single-cell DNA methylation and 3D genome architecture in the human brain.
  70. Mitochondria: A Potential Rejuvenation Tool against Aging.
  71. Glucocerebrosidase mutations disrupt the lysosome and now the mitochondria.
  1. Elife. 2023 Oct 12. pii: RP88084. [Epub ahead of print]12
    Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes.
    Michele Brischigliaro, Alfredo Cabrera-Orefice, Susanne Arnold, Carlo Viscomi, Massimo Zeviani, Erika Fernández-Vizarra.
      Mammalian mitochondrial respiratory chain (MRC) complexes are able to associate into quaternary structures named supercomplexes (SCs), which normally coexist with non-bound individual complexes. The functional significance of SCs has not been fully clarified and the debate has been centered on whether or not they confer catalytic advantages compared with the non-bound individual complexes. Mitochondrial respiratory chain organization does not seem to be conserved in all organisms. In fact, and differently from mammalian species, mitochondria from Drosophila melanogaster tissues are characterized by low amounts of SCs, despite the high metabolic demands and MRC activity shown by these mitochondria. Here, we show that attenuating the biogenesis of individual respiratory chain complexes was accompanied by increased formation of stable SCs, which are missing in Drosophila melanogaster in physiological conditions. This phenomenon was not accompanied by an increase in mitochondrial respiratory activity. Therefore, we conclude that SC formation is necessary to stabilize the complexes in suboptimal biogenesis conditions, but not for the enhancement of respiratory chain catalysis.
    Keywords:  D. melanogaster; Drosophila; Mitochondria; OXPHOS; biochemistry; chemical biology; supercomplexes
    DOI:  https://doi.org/10.7554/eLife.88084
  2. Endocr Metab Immune Disord Drug Targets. 2023 Oct 04.
    Diversities in Leigh Syndrome Associated with MT-ATP6 Gene Variants.
    Sara Martins, Maria João Santos, Marta Simões, Sandra Jacinto, Cristina Martins Halpern, Juliette Dupont, Luísa Diogo, Manuela Grazina.
       INTRODUCTION: Leigh syndrome (LS) is clinically and genetically heterogeneous and presents defective mitochondrial bioenergetics. Patients present neurological symptoms and imagiological features that may result in early death [1]. The LS has been associated with mitochondrial DNA (mtDNA) variants, e.g., m.8993T>G (L156R) and m.8993T>C (L156P), in the MT-ATP6 gene. They lead to the substitution of a highly conserved amino acid in subunit 6 of ATP synthase, affecting the F0 domain and ATP synthesis [1-3]. We present five cases with m.8993T>G and a family harbouring m.8993T>C+m.1555A>G (proband and four relatives).
    METHODS: Our laboratory received 48 samples from LS-suspected patients. The samples (various tissues) were assessed for bioenergetics (activity of mitochondrial respiratory chain (MRC) complexes, ubiquinone content) and genetic analyses (mtDNA copy number, Sequencing and PCR-RFLP) by established protocols.
    RESULTS/CASE REPORT: Bioenergetics were assessed in 5 patients (various tissues) with varying levels of MRC/ATP synthase impairment. Six cases had a mtDNA pathogenic variant in the 8993 nucleotide associated with LS. Five cases presented the m.8993T>G variant, one of which (P5) possibly de novo. This variant was homoplasmy (P1-3) or very high heteroplasmy (P4/5, 90-95%). Of the four patients with bioenergetics assessment, three (P1/3/4) had deficiencies of MRC complexes, and P5 had small deficits. The other case (familial, proband and 4 relatives) presented a combination of m.1555A>G (homoplasmy) and m.8993T>C (heteroplasmy) variants. The proband presents m.8993T>C in 95% heteroplasmy and 85-35% in three relatives. All have m.1555A>G in homoplasmy, including the fourth relative without m.8993T>C. A deficiency (31%) was found in complex V activity in muscle for proband.
    CONCLUSION: We present a case series of patients harbouring pathogenic variants in the 8993 nucleotide of mtDNA, which have been associated with LS and impairment of MRC's complex V. These cases highlight the variability in clinical symptoms and their severity, as well as genetic heterogeneity within LS. Many patients will not present a classic pathogenic variant and there are many cases of asymptomatic relatives (carriers). It is important to get a broader view of the cases - classical methods and multiple tissue analysis are still valuable tools for the comprehensive characterization of patients.
    Keywords:  Leigh syndrome; disease heterogeneity; methodology; mitochondrial cytopathies; mtDNA; pathogenic sequence variants
    DOI:  https://doi.org/10.2174/0118715303273271230928060000
  3. EMBO Rep. 2023 Oct 11. e57228
    Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.
    Conor T Ronayne, Thomas D Jackson, Christopher F Bennett, Elizabeth A Perry, Noa Kantorovic, Pere Puigserver.
      Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations is redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. One method to rescue this cell death vulnerability is the inhibition of mitochondrial translation using tetracyclines. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that tetracyclines inhibit the mitochondrial ribosome and promote survival through suppression of endoplasmic reticulum (ER) stress. Tetracyclines increase mitochondrial levels of the mitoribosome quality control factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) and promote its recruitment to the mitoribosome large subunit, where MALSU1 is necessary for tetracycline-induced survival and suppression of ER stress. Glucose starvation induces ER stress to activate the unfolded protein response and IRE1α-mediated cell death that is inhibited by tetracyclines. These studies establish a new interorganelle communication whereby inhibition of the mitoribosome signals to the ER to promote survival, implicating basic mechanisms of cell survival and treatment of mitochondrial diseases.
    Keywords:  IRE1α; MALSU1; mitochondrial disease; mitoribosome; tetracyclines
    DOI:  https://doi.org/10.15252/embr.202357228
  4. Hum Mol Genet. 2023 Oct 10. pii: ddad161. [Epub ahead of print]
    CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature.
    Mario K Shammas, Yu Nie, Alexandra Gilsrud, Xiaoping Huang, Derek P Narendra, Patrick F Chinnery.
      Mutations affecting the mitochondrial intermembrane space protein CHCHD10 cause human disease, but it is not known why different amino acid substitutions cause markedly different clinical phenotypes, including amyotrophic lateral sclerosis-frontotemporal dementia, spinal muscular atrophy Jokela-type, isolated autosomal dominant mitochondrial myopathy and cardiomyopathy. CHCHD10 mutations have been associated with deletions of mitochondrial DNA (mtDNA deletions), raising the possibility that these explain the clinical variability. Here, we sequenced mtDNA obtained from hearts, skeletal muscle, livers and spinal cords of WT and Chchd10 G58R or S59L knockin mice to characterize the mtDNA deletion signatures of the two mutant lines. We found that the deletion levels were higher in G58R and S59L mice than in WT mice in some tissues depending on the Chchd10 genotype, and the deletion burden increased with age. Furthermore, we observed that the spinal cord was less prone to the development of mtDNA deletions than the other tissues examined. Finally, in addition to accelerating the rate of naturally occurring deletions, Chchd10 mutations also led to the accumulation of a novel set of deletions characterized by shorter direct repeats flanking the deletion breakpoints. Our results indicate that Chchd10 mutations in mice induce tissue-specific deletions which may also contribute to the clinical phenotype associated with these mutations in humans.
    Keywords:  miochondrial DNA; mitochondria; mtDNA deletions; neurodegeneration
    DOI:  https://doi.org/10.1093/hmg/ddad161
  5. Nat Metab. 2023 Oct 09.
    COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.
    Sukanya Guhathakurta, Niyazi Umut Erdogdu, Juliane J Hoffmann, Iga Grzadzielewska, Alexander Schendzielorz, Janine Seyfferth, Christoph U Mårtensson, Mauro Corrado, Adam Karoutas, Bettina Warscheid, Nikolaus Pfanner, Thomas Becker, Asifa Akhtar.
      Reversible acetylation of mitochondrial proteins is a regulatory mechanism central to adaptive metabolic responses. Yet, how such functionally relevant protein acetylation is achieved remains unexplored. Here we reveal an unprecedented role of the MYST family lysine acetyltransferase MOF in energy metabolism via mitochondrial protein acetylation. Loss of MOF-KANSL complex members leads to mitochondrial defects including fragmentation, reduced cristae density and impaired mitochondrial electron transport chain complex IV integrity in primary mouse embryonic fibroblasts. We demonstrate COX17, a complex IV assembly factor, as a bona fide acetylation target of MOF. Loss of COX17 or expression of its non-acetylatable mutant phenocopies the mitochondrial defects observed upon MOF depletion. The acetylation-mimetic COX17 rescues these defects and maintains complex IV activity even in the absence of MOF, suggesting an activatory role of mitochondrial electron transport chain protein acetylation. Fibroblasts from patients with MOF syndrome who have intellectual disability also revealed respiratory defects that could be restored by alternative oxidase, acetylation-mimetic COX17 or mitochondrially targeted MOF. Overall, our findings highlight the critical role of MOF-KANSL complex in mitochondrial physiology and provide new insights into MOF syndrome.
    DOI:  https://doi.org/10.1038/s42255-023-00904-w
  6. Glob Med Genet. 2023 Dec;10(4): 278-281
    The First Reported Case of a Child with Two Different Rare Metabolic Disorders: Very Long-Chain Acyl-CoA Dehydrogenase Deficiency and Encephalomyopathic Mitochondrial DNA Depletion Syndrome 13.
    Maha Alotaibi, Amal Alqasmi, Faisal Albassam, Turki Alkahtani, Muath Alqahtany, Mohammed Alkhaldi.
      One of the most common inborn errors in fatty acid β oxidation (FAO) is a very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency. It is autosomal recessive. The enzyme used in the first phase of FAO is VLCAD. The enzyme is responsible for β oxidation spiral pathway's initial step, the dehydrogenation process of long-chain fatty acyl-CoA. The phenotypes include hypoglycemia, hepatomegaly, cardiomyopathy, and occasionally abrupt mortality. Most VLCAD deficiencies in newborns are now detected during the neonatal period due to the development of newborn screening programs. Mitochondrial DNA depletion syndromes (MTDPS) are one of the rarest metabolic disorders. It is an autosomal recessive disease caused by defects in genes necessary for the maintenance of mitochondrial DNA (mtDNA). One of these FBXL4 (F-box and leucine-rich repeat protein 4) variants causes encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13), which presents as a failure to thrive, severe global developmental delay, hypotonia, early infantile onset of encephalopathy, and lactic acidosis. We report here the case of a Saudi infant born to consanguineous parents who presented to us with severe failure to thrive, profound neurodevelopmental delays, and facial dysmorphic features. Whole-exome sequencing (WES) showed the infants had MTDPS13. The FBXL4 variant c.1698A > G p. (Ile566Met) has previously been described as a disease that causes developmental delay and lactic acidosis, and another variant has also been detected in the patient. The ACADVL variant c.134C > A p. (Ser45*) has previously been described to cause VLCAD deficiency. A comprehensive literature review showed our patient to be the first case of MTDPS13 and VLCAD reported to date worldwide.
    Keywords:  FBXL4; hypoglycemia; mitochondrial DNA; mitochondrial diseases; pediatric genetics; very long-chain acyl-CoA dehydrogenase deficiency
    DOI:  https://doi.org/10.1055/s-0043-1775979
  7. EMBO Rep. 2023 Oct 12. e57092
    The functional significance of mitochondrial respiratory chain supercomplexes.
    Andreas Kohler, Antoni Barrientos, Flavia Fontanesi, Martin Ott.
      The mitochondrial respiratory chain (MRC) is a key energy transducer in eukaryotic cells. Four respiratory chain complexes cooperate in the transfer of electrons derived from various metabolic pathways to molecular oxygen, thereby establishing an electrochemical gradient over the inner mitochondrial membrane that powers ATP synthesis. This electron transport relies on mobile electron carries that functionally connect the complexes. While the individual complexes can operate independently, they are in situ organized into large assemblies termed respiratory supercomplexes. Recent structural and functional studies have provided some answers to the question of whether the supercomplex organization confers an advantage for cellular energy conversion. However, the jury is still out, regarding the universality of these claims. In this review, we discuss the current knowledge on the functional significance of MRC supercomplexes, highlight experimental limitations, and suggest potential new strategies to overcome these obstacles.
    Keywords:  Mitochondria; bioenergetics; electron transfer; respiratory chain; supercomplexes
    DOI:  https://doi.org/10.15252/embr.202357092
  8. Mol Cell. 2023 Oct 08. pii: S1097-2765(23)00753-0. [Epub ahead of print]
    Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis.
    Yi Fu, Olivia Sacco, Emily DeBitetto, Evgeny Kanshin, Beatrix Ueberheide, Agnel Sfeir.
      Mitochondrial DNA double-strand breaks (mtDSBs) lead to the degradation of circular genomes and a reduction in copy number; yet, the cellular response in human cells remains elusive. Here, using mitochondrial-targeted restriction enzymes, we show that a subset of cells with mtDSBs exhibited defective mitochondrial protein import, reduced respiratory complexes, and loss of membrane potential. Electron microscopy confirmed the altered mitochondrial membrane and cristae ultrastructure. Intriguingly, mtDSBs triggered the integrated stress response (ISR) via the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) by DELE1 and heme-regulated eIF2α kinase (HRI). When ISR was inhibited, the cells experienced intensified mitochondrial defects and slower mtDNA recovery post-breakage. Lastly, through proteomics, we identified ATAD3A-a membrane-bound protein interacting with nucleoids-as potentially pivotal in relaying signals from impaired genomes to the inner mitochondrial membrane. In summary, our study delineates the cascade connecting damaged mitochondrial genomes to the cytoplasm and highlights the significance of the ISR in maintaining mitochondrial homeostasis amid genome instability.
    Keywords:  ATAD3A; double-strand breaks; integrated stress response; mitochondrial DNA; protein import
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.026
  9. Nat Commun. 2023 Oct 13. 14(1): 6431
    PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.
    Natalie M Niemi, Lia R Serrano, Laura K Muehlbauer, Catherine E Balnis, Lianjie Wei, Andrew J Smith, Keri-Lyn Kozul, Merima Forny, Olivia M Connor, Edrees H Rashan, Evgenia Shishkova, Kathryn L Schueler, Mark P Keller, Alan D Attie, Jonathan R Friedman, Julia K Pagan, Joshua J Coon, David J Pagliarini.
      PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass and metabolic capacity with elevated hepatic triglyceride accumulation. Pptc7 knockout animals exhibit increased expression of the mitophagy receptors BNIP3 and NIX, and Pptc7-/- mouse embryonic fibroblasts (MEFs) display a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs, including multiple sites on BNIP3 and NIX, and our molecular studies demonstrate that PPTC7 can directly interact with and dephosphorylate these proteins. These data suggest that Pptc7 deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that PPTC7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for PPTC7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.
    DOI:  https://doi.org/10.1038/s41467-023-42069-w
  10. Nat Cell Biol. 2023 Oct 09.
    Hem25p is required for mitochondrial IPP transport in fungi.
    Jonathan Tai, Rachel M Guerra, Sean W Rogers, Zixiang Fang, Laura K Muehlbauer, Evgenia Shishkova, Katherine A Overmyer, Joshua J Coon, David J Pagliarini.
      Coenzyme Q (CoQ, ubiquinone) is an essential cellular cofactor composed of a redox-active quinone head group and a long hydrophobic polyisoprene tail. How mitochondria access cytosolic isoprenoids for CoQ biosynthesis is a longstanding mystery. Here, via a combination of genetic screening, metabolic tracing and targeted uptake assays, we reveal that Hem25p-a mitochondrial glycine transporter required for haem biosynthesis-doubles as an isopentenyl pyrophosphate (IPP) transporter in Saccharomyces cerevisiae. Mitochondria lacking Hem25p failed to efficiently incorporate IPP into early CoQ precursors, leading to loss of CoQ and turnover of CoQ biosynthetic proteins. Expression of Hem25p in Escherichia coli enabled robust IPP uptake and incorporation into the CoQ biosynthetic pathway. HEM25 orthologues from diverse fungi, but not from metazoans, were able to rescue hem25∆ CoQ deficiency. Collectively, our work reveals that Hem25p drives the bulk of mitochondrial isoprenoid transport for CoQ biosynthesis in fungi.
    DOI:  https://doi.org/10.1038/s41556-023-01250-5
  11. Ageing Res Rev. 2023 Oct 11. pii: S1568-1637(23)00246-5. [Epub ahead of print] 102087
    Exercise mitigates Age-related Metabolic Diseases by improving Mitochondrial Dysfunction.
    Dandan Jia, Zhenjun Tian, Ru Wang.
      The benefits of regular physical activity are related to delaying and reversing the onset of ageing and age-related disorders, including cardiomyopathy, neurodegenerative diseases, cancer, obesity, diabetes, and fatty liver diseases. However, the molecular mechanisms of the benefits of exercise or physical activity on ageing and age-related disorders remain poorly understood. Mitochondrial dysfunction is implicated in the pathogenesis of ageing and age-related metabolic diseases. Mitochondrial health is an important mediator of cellular function. Therefore, exercise alleviates metabolic diseases in individuals with advancing ageing and age-related diseases by the remarkable promotion of mitochondrial biogenesis and function. Exerkines are identified as signaling moieties released in response to exercise. Exerkines released by exercise have potential roles in improving mitochondrial dysfunction in response to age-related disorders. This review comprehensive summarizes the benefits of exercise in metabolic diseases, linking mitochondrial dysfunction to the onset of age-related diseases. Using relevant examples utilizing this approach, the possibility of designing therapeutic interventions based on these molecular mechanisms is addressed.
    Keywords:  age-related diseases; ageing; exerkines; mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.arr.2023.102087
  12. Brain. 2023 Oct 07. pii: awad347. [Epub ahead of print]
    Homozygous MFN2 variants causing severe antenatal encephalopathy with clumped mitochondria.
    Arnaud Chevrollier, Adeline Alice Bonnard, Lyse Ruaud, Naïg Gueguen, Laurence Perrin, Valérie Desquiret-Dumas, Fabien Guimiot, Pierre-Hadrien Becker, Jonathan Levy, Pascal Reynier, Pauline Gaignard.
      Pathogenic variants in MFN2 gene are commonly associated with autosomal dominant (CMT2A2A) or recessive (CMT2A2B) Charcot-Marie-Tooth disease, with possible involvement of the central nervous system. Here, we present a case of severe antenatal encephalopathy with lissencephaly, polymicrogyria and cerebellar atrophy. Whole Genome Analysis revealed a homozygous deletion c.1717-274_1734 del (NM_014874.4) in MFN2 gene, leading to exon 16 skipping and in-frame loss of 50 amino acids (p.Gln574_Val624del), removing the proline rich domain and the transmembrane domain 1 (TM1). MFN2 is a transmembrane GTPase located on the mitochondrial outer membrane (MOM) that contributes to mitochondrial fusion, shaping large mitochondrial networks within cells. In silico modelling showed that the loss of the TM1 domain resulted in a drastically altered topological insertion of the protein in the MOM. Fetus fibroblasts, investigated by fluorescent cell imaging, electron microscopy and time lapse recording, showed a sharp alteration of the mitochondrial network, with clumped mitochondria and clusters of tethered mitochondria unable to fuse. Multiple deficiencies of respiratory chain complexes with severe impairment of complex I were also evidenced in patient fibroblasts, without involvement of mitochondrial DNA instability. This is the first reported case of a severe developmental defect due to MFN2 deficiency with clumped mitochondria.
    Keywords:  early onset; mitochondrial dynamics; mitochondrial fusion; neurological disorders
    DOI:  https://doi.org/10.1093/brain/awad347
  13. Nat Commun. 2023 10 10. 14(1): 6344
    FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes.
    Jiamin Qiu, Feng Yue, Peipei Zhu, Jingjuan Chen, Fan Xu, Lijia Zhang, Kun Ho Kim, Madigan M Snyder, Nanjian Luo, Hao-Wei Xu, Fang Huang, W Andy Tao, Shihuan Kuang.
      Cold stimulation dynamically remodels mitochondria in brown adipose tissue (BAT) to facilitate non-shivering thermogenesis in mammals, but what regulates mitochondrial plasticity is poorly understood. Comparing mitochondrial proteomes in response to cold revealed FAM210A as a cold-inducible mitochondrial inner membrane protein. An adipocyte-specific constitutive knockout of Fam210a (Fam210aAKO) disrupts mitochondrial cristae structure and diminishes the thermogenic activity of BAT, rendering the Fam210aAKO mice vulnerable to lethal hypothermia under acute cold exposure. Induced knockout of Fam210a in adult adipocytes (Fam210aiAKO) does not affect steady-state mitochondrial structure under thermoneutrality, but impairs cold-induced mitochondrial remodeling, leading to progressive loss of cristae and reduction of mitochondrial density. Proteomics reveals an association between FAM210A and OPA1, whose cleavage governs cristae dynamics and mitochondrial remodeling. Mechanistically, FAM210A interacts with mitochondrial protease YME1L and modulates its activity toward OMA1 and OPA1 cleavage. These data establish FAM210A as a key regulator of mitochondrial cristae remodeling in BAT and shed light on the mechanism underlying mitochondrial plasticity in response to cold.
    DOI:  https://doi.org/10.1038/s41467-023-41988-y
  14. Nucleic Acids Res. 2023 Oct 12. pii: gkad842. [Epub ahead of print]
    BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome.
    Hui Zhong, Alexandre Janer, Oleh Khalimonchuk, Hana Antonicka, Eric A Shoubridge, Antoni Barrientos.
      The human mitochondrial ribosome contains three [2Fe-2S] clusters whose assembly pathway, role, and implications for mitochondrial and metabolic diseases are unknown. Here, structure-function correlation studies show that the clusters play a structural role during mitoribosome assembly. To uncover the assembly pathway, we have examined the effect of silencing the expression of Fe-S cluster biosynthetic and delivery factors on mitoribosome stability. We find that the mitoribosome receives its [2Fe-2S] clusters from the GLRX5-BOLA3 node. Additionally, the assembly of the small subunit depends on the mitoribosome biogenesis factor METTL17, recently reported containing a [4Fe-4S] cluster, which we propose is inserted via the ISCA1-NFU1 node. Consistently, fibroblasts from subjects suffering from 'multiple mitochondrial dysfunction' syndrome due to mutations in BOLA3 or NFU1 display previously unrecognized attenuation of mitochondrial protein synthesis that contributes to their cellular and pathophysiological phenotypes. Finally, we report that, in addition to their structural role, one of the mitoribosomal [2Fe-2S] clusters and the [4Fe-4S] cluster in mitoribosome assembly factor METTL17 sense changes in the redox environment, thus providing a way to regulate organellar protein synthesis accordingly.
    DOI:  https://doi.org/10.1093/nar/gkad842
  15. iScience. 2023 Oct 20. 26(10): 107955
    Drosophila Mpv17 forms an ion channel and regulates energy metabolism.
    Samantha Corrà, Vanessa Checchetto, Michele Brischigliaro, Chiara Rampazzo, Emanuela Bottani, Cristina Gagliani, Katia Cortese, Cristiano De Pittà, Marco Roverso, Diego De Stefani, Sara Bogialli, Massimo Zeviani, Carlo Viscomi, Ildiko Szabò, Rodolfo Costa.
      Mutations in MPV17 are a major contributor to mitochondrial DNA (mtDNA) depletion syndromes, a group of inherited genetic conditions due to mtDNA instability. To investigate the role of MPV17 in mtDNA maintenance, we generated and characterized a Drosophila melanogaster Mpv17 (dMpv17) KO model showing that the absence of dMpv17 caused profound mtDNA depletion in the fat body but not in other tissues, increased glycolytic flux and reduced lifespan in starvation. Accordingly, the expression of key genes of glycogenolysis and glycolysis was upregulated in dMpv17 KO flies. In addition, we demonstrated that dMpv17 formed a channel in planar lipid bilayers at physiological ionic conditions, and its electrophysiological hallmarks were affected by pathological mutations. Importantly, the reconstituted channel translocated uridine but not orotate across the membrane. Our results indicate that dMpv17 forms a channel involved in translocation of key metabolites and highlight the importance of dMpv17 in energy homeostasis and mitochondrial function.
    Keywords:  model organism; molecular biology; physiology
    DOI:  https://doi.org/10.1016/j.isci.2023.107955
  16. Nature. 2023 Oct 11.
    Apoptotic stress causes mtDNA release during senescence and drives the SASP.
    Stella Victorelli, Hanna Salmonowicz, James Chapman, Helene Martini, Maria Grazia Vizioli, Joel S Riley, Catherine Cloix, Ella Hall-Younger, Jair Machado Espindola-Netto, Diana Jurk, Anthony B Lagnado, Lilian Sales Gomez, Joshua N Farr, Dominik Saul, Rebecca Reed, George Kelly, Madeline Eppard, Laura C Greaves, Zhixun Dou, Nicholas Pirius, Karolina Szczepanowska, Rebecca A Porritt, Huijie Huang, Timothy Y Huang, Derek A Mann, Claudio Akio Masuda, Sundeep Khosla, Haiming Dai, Scott H Kaufmann, Emmanouil Zacharioudakis, Evripidis Gavathiotis, Nathan K LeBrasseur, Xue Lei, Alva G Sainz, Viktor I Korolchuk, Peter D Adams, Gerald S Shadel, Stephen W G Tait, João F Passos.
      Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.
    DOI:  https://doi.org/10.1038/s41586-023-06621-4
  17. J Neurol. 2023 Oct 13.
    Current management of primary mitochondrial disorders in EU countries: the European Reference Networks survey.
    Michelangelo Mancuso, Piervito Lopriore, Costanza Lamperti, Thomas Klopstock, Shamima Rahman, Laura Licchetta, Cornelia Kornblum, Saskia B Wortmann, Hélène Dollfus, Maria T Papadopoulou, Alexis Arzimanoglou, Maurizio Scarpa, Holm Graessner, Teresinha Evangelista.
       BACKGROUND AND PURPOSE: Primary mitochondrial diseases (PMDs) are rare diseases for which diagnosis is challenging, and management and training programs are not well defined in Europe. To capture and assess care needs, five different European Reference Networks have conducted an exploratory survey.
    METHODS: The survey covering multiple topics relating to PMDs was sent to all ERNs healthcare providers (HCPs) in Europe.
    RESULTS: We have collected answers from 220 members based in 24/27 European member states and seven non-European member states. Even though most of the responders are aware of neurogenetic diseases, difficulties arise in the ability to deliver comprehensive genetic testing. While single gene analysis is widely available in Europe, whole exome and genome sequencing are not easily accessible, with considerable variation between countries and average waiting time for results frequently above 6 months. Only 12.7% of responders were happy with the ICD-10 codes for classifying patients with PMDs discharged from the hospital, and more than 70% of them consider that PMDs deserve specific ICD codes to improve clinical management, including tailored healthcare, and for reimbursement reasons. Finally, 90% of responders declared that there is a need for further education and training in these diseases.
    CONCLUSIONS: This survey provides information on the current difficulties in the care of PMDs in Europe. We believe that the results of this survey are important to help rare disease stakeholders in European countries identify key care and research priorities.
    Keywords:  Europe; European Reference Networks; Mitochondrial diseases; Rare diseases; Survey
    DOI:  https://doi.org/10.1007/s00415-023-12017-1
  18. Brain. 2023 Oct 07. pii: awad340. [Epub ahead of print]
    Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.
    Camilla Aurora Franchino, Martina Brughera, Valentina Baderna, Daniele De Ritis, Alessandra Rocco, Sara Seneca, Luc Regal, Paola Podini, Maurizio D'Antonio, Camilo Toro, Angelo Quattrini, Emmanuel Scalais, Francesca Maltecca.
      AFG3L2 is a mitochondrial protease exerting protein quality control in the inner mitochondrial membrane (IMM). Heterozygous AFG3L2 mutations cause Spinocerebellar Ataxia type 28 (SCA28) or Dominant Optic Atrophy type 12 (DOA12), while biallelic AFG3L2 mutations result in the rare and severe Spastic Ataxia type 5 (SPAX5). The clinical spectrum of SPAX5 includes childhood-onset cerebellar ataxia, spasticity, dystonia, and myoclonic epilepsy. We previously reported that the absence or mutation of AFG3L2 leads to the accumulation of mitochondria-encoded proteins, causing the over-activation of the stress-sensitive protease OMA1, which over-processes OPA1, leading to mitochondrial fragmentation. Recently, OMA1 has been identified as the pivotal player communicating mitochondrial stress to the cytosol via a pathway involving the IMM protein DELE1 and the cytosolic kinase HRI, thus eliciting the integrated stress response (ISR). In general, the ISR reduces global protein synthesis and drives the expression of cytoprotective genes that allow cells to endure proteotoxic stress. However, the relevance of the OMA1-DELE1-HRI axis in vivo, and especially in a human CNS disease context, has been poorly documented so far. In this work, we demonstrated that mitochondrial proteotoxicity in the absence/mutation of AFG3L2 activates the OMA1-DELE1-HRI pathway eliciting the ISR. We indeed found enhanced OMA1-dependent processing of DELE1 upon depletion of AFG3L2. Also, in both skin fibroblasts from SPAX5 patients (including a novel case) and in the cerebellum of Afg3l2-/- mice we detected increased phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2α), increased levels of ATF4 and strong upregulation of its downstream targets (Chop, Chac1, Ppp1r15a and Ffg21). Silencing of DELE1 or HRI in SPAX5 fibroblasts (where OMA1 is overactivated at basal state) reduces eIF2α phosphorylation and affects cell growth. In agreement, pharmacological potentiation of ISR via Sephin-1, a drug that selectively inhibits the stress-induced eIF2alpha phosphatase GADD34 (encoded by Ppp1r15a), improved cell growth of SPAX5 fibroblasts, and cell survival and dendritic arborization ex vivo in primary Afg3l2-/- Purkinje neurons (PNs). Notably, Sephin-1 treatment in vivo extended the life span of Afg3l2-/- mice, improved PN morphology, mitochondrial ultrastructure and respiratory capacity. These data indicate that activation of the OMA1-DELE1-HRI pathway is protective in the context of SPAX5. Pharmacological tuning of the ISR may represent a future therapeutic strategy for SPAX5 and other cerebellar ataxias caused by impaired mitochondrial proteostasis.
    Keywords:  OMA1; integrated stress response; spastic ataxia type 5
    DOI:  https://doi.org/10.1093/brain/awad340
  19. J Biomed Sci. 2023 Oct 08. 30(1): 85
    Extracellular release in the quality control of the mammalian mitochondria.
    Kuei-Hsiang Pan, Hung Chang, Wei Yuan Yang.
      Mammalian cells release a wealth of materials to their surroundings. Emerging data suggest these materials can even be mitochondria with perturbed morphology and aberrant function. These dysfunctional mitochondria are removed by migrating cells through membrane shedding. Neuronal cells, cardiomyocytes, and adipocytes send dysfunctional mitochondria into the extracellular space for nearby cells to degrade. Various studies also indicate that there is an interplay between intracellular mitochondrial degradation pathways and mitochondrial release in handling dysfunctional mitochondria. These observations, in aggregate, suggest that extracellular release plays a role in quality-controlling mammalian mitochondria. Future studies will help delineate the various types of molecular machinery mammalian cells use to release dysfunctional mitochondria. Through the studies, we will better understand how mammalian cells choose between intracellular degradation and extracellular release for the quality control of mitochondria.
    Keywords:  Autophagy; Extracellular vesicles; Mitochondria; Mitophagy; Organelle quality control
    DOI:  https://doi.org/10.1186/s12929-023-00979-3
  20. Orphanet J Rare Dis. 2023 Oct 11. 18(1): 320
    The burden of mitochondrial disease with associated seizures: systematic literature reviews of health-related quality of life, utilities, costs and healthcare resource use data.
    Enrico Bertini, Emily Gregg, Chris Bartlett, Vij Senthilnathan, Mick Arber, Deborah Watkins, Sara Graziadio, Ioannis Tomazos.
       BACKGROUND: Mitochondrial disease is a degenerative, progressive, heterogeneous group of genetic disorders affecting children and adults. Mitochondrial disease is associated with morbidity and mortality, with predominantly neurological and neuromuscular symptoms including dystonia, weakness, encephalopathy, developmental delay and seizures. Seizures are one of the most common and severe manifestations of mitochondrial disease. These seizures are typically refractory to common anti-seizure therapies. There are no approved disease-modifying treatments for mitochondrial disease. Our objective was to conduct two systematic literature reviews to identify health-related quality of life (HRQoL), utilities, costs and healthcare resource use data in mitochondrial disease with associated seizures.
    METHODS: A range of databases and information sources were searched up to July 2022 to identify eligible studies. Search strategies included a range of variant terms for mitochondrial disease and HRQoL, utilities, cost and healthcare resource use outcomes. Two reviewers independently assessed articles against the eligibility criteria; studies were extracted by one reviewer and checked by a second. Risk of bias was assessed for studies reporting HRQoL data. Results were narratively assessed.
    RESULTS: Seven studies were eligible for the HRQoL and utilities review. The studies used different tools to report data, and despite the variability in methods, HRQoL scores across the studies showed moderate/severe disease in patients with mitochondrial disease with associated seizures. Parents of patients with mitochondrial disease with associated seizures were characterised by high total parenting stress. No studies reported utilities data. Two case reports and one retrospective review of medical records of children who died in hospital were eligible for the costs and resource use review. These provided limited information on the duration of hospital stay, in an intensive care unit (ICU), on mechanical ventilation. No studies reported costs data.
    CONCLUSION: These reviews highlight the limited HRQoL, utilities, costs and resource use data and the variability of instruments used in mitochondrial disease with associated seizures. However, the data available indicate that mitochondrial disease with associated seizures affects patients' and caregivers' HRQoL alike. No robust conclusion can be drawn on the impact of mitochondrial disease with associated seizures on hospital or ICU length of stay. Trial registration PROSPERO: CRD42022345005.
    Keywords:  Costs; Disease burden; Epilepsy; Health state utility values; Health-related quality of life; Healthcare resource use; Mitochondrial diseases; Seizures; Systematic literature reviews; Utilities
    DOI:  https://doi.org/10.1186/s13023-023-02945-6
  21. J Biomed Sci. 2023 Oct 12. 30(1): 86
    Crosstalk between mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis.
    Lei Liu, Yanjun Li, Guo Chen, Quan Chen.
      Mitochondrial mass and quality are tightly regulated by two essential and opposing mechanisms, mitochondrial biogenesis (mitobiogenesis) and mitophagy, in response to cellular energy needs and other cellular and environmental cues. Great strides have been made to uncover key regulators of these complex processes. Emerging evidence has shown that there exists a tight coordination between mitophagy and mitobiogenesis, and their defects may cause many human diseases. In this review, we will first summarize the recent advances made in the discovery of molecular regulations of mitobiogenesis and mitophagy and then focus on the mechanism and signaling pathways involved in the simultaneous regulation of mitobiogenesis and mitophagy in the response of tissue or cultured cells to energy needs, stress, or pathophysiological conditions. Further studies of the crosstalk of these two opposing processes at the molecular level will provide a better understanding of how the cell maintains optimal cellular fitness and function under physiological and pathophysiological conditions, which holds promise for fighting aging and aging-related diseases.
    Keywords:  Aging; Aging-related diseases; Mitochondrial biogenesis; Mitochondrial quality; Mitophagy; Mitophagy receptors
    DOI:  https://doi.org/10.1186/s12929-023-00975-7
  22. Front Endocrinol (Lausanne). 2023 ;14 1264530
    The roles of FGF21 and GDF15 in mediating the mitochondrial integrated stress response.
    Jayashree Jena, Luis Miguel García-Peña, Renata O Pereira.
      Various models of mitochondrial stress result in induction of the stress-responsive cytokines fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). This is an adaptive mechanism downstream of the mitochondrial integrated stress response frequently associated with improvements in systemic metabolic health. Both FGF21 and GDF15 have been shown to modulate energy balance and glucose homeostasis, and their pharmacological administration leads to promising beneficial effects against obesity and associated metabolic diseases in pre-clinical models. Furthermore, endogenous upregulation of FGF21 and GDF15 is associated with resistance to diet-induced obesity (DIO), improved glucose homeostasis and increased insulin sensitivity. In this review, we highlight several studies on transgenic mouse models of mitochondrial stress and will compare the specific roles played by FGF21 and GDF15 on the systemic metabolic adaptations reported in these models.
    Keywords:  FGF21; GDF15; energy balance; integrated stress response; metabolic health; mitochondrial stress
    DOI:  https://doi.org/10.3389/fendo.2023.1264530
  23. Cell Rep. 2023 Oct 10. pii: S2211-1247(23)01253-6. [Epub ahead of print]42(10): 113241
    Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism.
    Makayla S Lancaster, Byungwook Kim, Emma H Doud, Mason D Tate, Ahmad D Sharify, Hongyu Gao, Duojiao Chen, Ed Simpson, Patrick Gillespie, Xiaona Chu, Marcus J Miller, Yue Wang, Yunlong Liu, Amber L Mosley, Jungsu Kim, Brett H Graham.
      Lysine succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the tricarboxylic acid cycle. Deficiency of succinyl-CoA synthetase (SCS), the tricarboxylic acid cycle enzyme catalyzing the interconversion of succinyl-CoA to succinate, results in mitochondrial encephalomyopathy in humans. This report presents a conditional forebrain-specific knockout (KO) mouse model of Sucla2, the gene encoding the ATP-specific beta isoform of SCS, resulting in postnatal deficiency of the entire SCS complex. Results demonstrate that accumulation of succinyl-CoA in the absence of SCS leads to hypersuccinylation within the murine cerebral cortex. Specifically, increased succinylation is associated with functionally significant reduced activity of respiratory chain complex I and widescale alterations in chromatin landscape and gene expression. Integrative analysis of the transcriptomic data also reveals perturbations in regulatory networks of neuronal transcription in the KO forebrain. Together, these findings provide evidence that protein succinylation plays a significant role in the pathogenesis of SCS deficiency.
    Keywords:  ATAC sequencing; CP: Metabolism; CP: Neuroscience; RNA sequencing; chromatin; electron transport chain; mass spectrometry; metabolism; neurons; post-translational modification; succinyl-CoA synthetase; succinylation
    DOI:  https://doi.org/10.1016/j.celrep.2023.113241
  24. Mol Cell Proteomics. 2023 Oct 05. pii: S1535-9476(23)00168-8. [Epub ahead of print] 100657
    Higher-order structural organization of the mitochondrial proteome charted by in situ cross-linking mass spectrometry.
    Johannes F Hevler, Albert J R Heck.
      Mitochondria are densely packed with proteins, of which most are involved physically or more transiently in protein-protein interactions (PPIs). Mitochondria host among others all enzymes of the Krebs cycle and the oxidative phosphorylation (OXPHOS) pathway and are foremost associated with cellular bioenergetics (1, 2). However, mitochondria are also important contributors to apoptotic cell death (3) and contain their own genome (4) indicating that they play additionally an eminent role in processes beyond bioenergetics (5). Despite intense efforts in identifying and characterizing mitochondrial protein complexes by structural biology and proteomics techniques, many PPIs have remained elusive. Several of these (membrane embedded) PPIs are less stable in-vitro hampering their characterization by most contemporary methods in structural biology. Particularly in these cases, cross-linking mass spectrometry (XL-MS) has proven valuable for the in-depth characterization of mitochondrial protein complexes in situ. Here, we highlight experimental strategies for the analysis of proteome-wide protein-protein interactions in mitochondria using XL-MS. We showcase the ability of in situ XL-MS as a tool to map sub-organelle interactions and topologies, and aid in refining structural models of protein complexes. We describe some of the most recent technological advances in XL-MS that may benefit the in situ characterization of PPIs even further, especially when combined with electron microscopy and structural modelling.
    Keywords:  In situ cross-linking mass spectrometry; cross-linking reagents; membrane complexes; mitochondria; protein localization; protein-protein interactions
    DOI:  https://doi.org/10.1016/j.mcpro.2023.100657
  25. Discov Med. 2023 Oct;35(178): 653-663
    Role of Mitochondrial Dysfunction in Cellular Lipid Homeostasis and Disease.
    Siresha Bathina, Undurti N Das.
      Mitochondria-associated membranes (MAMs) play a significant role in multiple cellular processes including lipid metabolism and neuronal survival. Fatty acids constitute 80% of the dry mass of the brain and are vital for life. Apart from mitochondrial β-oxidation, fatty acids are metabolized in part by peroxisomes to regulate the generation of acyl Coenzyme A and adenosine triphosphate (ATP). Ablation of mitochondria and its associated genes tether endoplasmic reticulum (ER)-Mitochondria contact and results in loss of function leading to aberrant lipid metabolism. Additionally, an increase in reactive oxygen species (ROS) levels along with free radicals' generation may lead to alteration in the integrity of membrane phospholipids, proteins, and DNA. Hence, it is critical to understand the effect of structural and functional aspects of mitochondria on lipid homeostasis. This review explains the role of mitochondrial dysfunction in lipid metabolism and its impact on various neurodegenerative diseases and metabolic disorders.
    Keywords:  lipid metabolism; mitochondria dysfunction; neurodegenerative disease
    DOI:  https://doi.org/10.24976/Discov.Med.202335178.64
  26. Georgian Med News. 2023 Jul-Aug;(340-341): 217-226
    THE ROLE OF GENETICS IN DISEASE DIAGNOSIS AND TREATMENT MITOCHONDRIAL RESPIRATORY CHAIN DYSREGULATION IN GENOMIC MEDICINE.
    G Patel M, B Varshini, A Mandal, D Krishna, V Rastogi, M Varma.
      Although mitochondrial DNA respiration circuit abnormalities are among the most common metabolic diseases to manifest in children, identification can be difficult due to their medical variability. Given the multisystem nature of the condition and its diverse and generalized manifestations, making a final diagnosis often takes a long time. Within this summary, they give an in-depth account of the physical signs of adolescent Mitochondrial Respiratory Chain Disorders (MRCDs),analyze the available diagnostics and treatment possibilities, and emphasize current developments in this field of study. During the discovery of fresh biomarkers and the development of next generation sequencing (NGS) technology, extensive research over the years has considerably enhanced the regularity that precise diagnoses are produced. Given the intricate nature of mitochondrial DNA biology and its double genomic investments, Sequencing has made significant progress in identifying the genetic basis of Mitochondrial Respiratory Chain Disorders (MRCDs). Research studies have been created employing a variety of various methods of therapy in an effort to shift the goal on therapy that is mainly curative to possibly having a positive impact on the natural course of the trouble. That's because there is gained a greater awareness of the underlying causes of this category of ailments.
  27. Nat Commun. 2023 Oct 10. 14(1): 6328
    Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.
    Tomas Venit, Oscar Sapkota, Wael Said Abdrabou, Palanikumar Loganathan, Renu Pasricha, Syed Raza Mahmood, Nadine Hosny El Said, Shimaa Sherif, Sneha Thomas, Salah Abdelrazig, Shady Amin, Davide Bedognetti, Youssef Idaghdour, Mazin Magzoub, Piergiorgio Percipalle.
      Metabolic reprogramming is one of the hallmarks of tumorigenesis. Here, we show that nuclear myosin 1 (NM1) serves as a key regulator of cellular metabolism. NM1 directly affects mitochondrial oxidative phosphorylation (OXPHOS) by regulating mitochondrial transcription factors TFAM and PGC1α, and its deletion leads to underdeveloped mitochondria inner cristae and mitochondrial redistribution within the cell. These changes are associated with reduced OXPHOS gene expression, decreased mitochondrial DNA copy number, and deregulated mitochondrial dynamics, which lead to metabolic reprogramming of NM1 KO cells from OXPHOS to aerobic glycolysis.This, in turn, is associated with a metabolomic profile typical for cancer cells, namely increased amino acid-, fatty acid-, and sugar metabolism, and increased glucose uptake, lactate production, and intracellular acidity. NM1 KO cells form solid tumors in a mouse model, suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient carcinogenic signal. We suggest that NM1 plays a role as a tumor suppressor and that NM1 depletion may contribute to the Warburg effect at the onset of tumorigenesis.
    DOI:  https://doi.org/10.1038/s41467-023-42093-w
  28. Mol Cell Biol. 2023 ;43(10): 531-546
    Mitochondrial Fragmentation Promotes Inflammation Resolution Responses in Macrophages via Histone Lactylation.
    Leah I Susser, My-Anh Nguyen, Michele Geoffrion, Christina Emerton, Mireille Ouimet, Mireille Khacho, Katey J Rayner.
      During the inflammatory response, macrophage phenotypes can be broadly classified as pro-inflammatory/classically activated "M1", or pro-resolving/alternatively "M2" macrophages. Although the classification of macrophages is general and assumes there are distinct phenotypes, in reality macrophages exist across a spectrum and must transform from a pro-inflammatory state to a proresolving state following an inflammatory insult. To adapt to changing metabolic needs of the cell, mitochondria undergo fusion and fission, which have important implications for cell fate and function. We hypothesized that mitochondrial fission and fusion directly contribute to macrophage function during the pro-inflammatory and proresolving phases. In the present study, we find that mitochondrial length directly contributes to macrophage phenotype, primarily during the transition from a pro-inflammatory to a proresolving state. Phenocopying the elongated mitochondrial network (by disabling the fission machinery using siRNA) leads to a baseline reduction in the inflammatory marker IL-1β, but a normal inflammatory response to LPS, similar to control macrophages. In contrast, in macrophages with a phenocopied fragmented phenotype (by disabling the fusion machinery using siRNA) there is a heightened inflammatory response to LPS and increased signaling through the ATF4/c-Jun transcriptional axis compared to control macrophages. Importantly, macrophages with a fragmented mitochondrial phenotype show increased expression of proresolving mediator arginase 1 and increased phagocytic capacity. Promoting mitochondrial fragmentation caused an increase in cellular lactate, and an increase in histone lactylation which caused an increase in arginase 1 expression. These studies demonstrate that a fragmented mitochondrial phenotype is critical for the proresolving response in macrophages and specifically drive epigenetic changes via lactylation of histones following an inflammatory insult.
    Keywords:  fission; fusion; histone lactylation; inflammation resolution; macrophages; mitochondrial metabolism
    DOI:  https://doi.org/10.1080/10985549.2023.2253131
  29. Sci Adv. 2023 Oct 13. 9(41): eadi1411
    Glial-derived mitochondrial signals affect neuronal proteostasis and aging.
    Raz Bar-Ziv, Naibedya Dutta, Adam Hruby, Edward Sukarto, Maxim Averbukh, Athena Alcala, Hope R Henderson, Jenni Durieux, Sarah U Tronnes, Qazi Ahmad, Theodore Bolas, Joel Perez, Julian G Dishart, Matthew Vega, Gilberto Garcia, Ryo Higuchi-Sanabria, Andrew Dillin.
      The nervous system plays a critical role in maintaining whole-organism homeostasis; neurons experiencing mitochondrial stress can coordinate the induction of protective cellular pathways, such as the mitochondrial unfolded protein response (UPRMT), between tissues. However, these studies largely ignored nonneuronal cells of the nervous system. Here, we found that UPRMT activation in four astrocyte-like glial cells in the nematode, Caenorhabditis elegans, can promote protein homeostasis by alleviating protein aggregation in neurons. Unexpectedly, we find that glial cells use small clear vesicles (SCVs) to signal to neurons, which then relay the signal to the periphery using dense-core vesicles (DCVs). This work underlines the importance of glia in establishing and regulating protein homeostasis within the nervous system, which can then affect neuron-mediated effects in organismal homeostasis and longevity.
    DOI:  https://doi.org/10.1126/sciadv.adi1411
  30. Aging Dis. 2023 Sep 26.
    The Emerging Role of the Mitochondrial Respiratory Chain in Skeletal Aging.
    Huaqiang Tao, Pengfei Zhu, Wenyu Xia, Miao Chu, Kai Chen, Qiufei Wang, Ye Gu, Xiaomin Lu, Jiaxiang Bai, Dechun Geng.
      Maintenance of mitochondrial homeostasis is crucial for ensuring healthy mitochondria and normal cellular function. This process is primarily responsible for regulating processes that include mitochondrial OXPHOS, which generates ATP, as well as mitochondrial oxidative stress, apoptosis, calcium homeostasis, and mitophagy. Bone mesenchymal stem cells express factors that aid in bone formation and vascular growth. Positive regulation of hematopoietic stem cells in the bone marrow affects the differentiation of osteoclasts. Furthermore, the metabolic regulation of cells that play fundamental roles in various regions of the bone, as well as interactions within the bone microenvironment, actively participates in regulating bone integrity and aging. The maintenance of cellular homeostasis is dependent on the regulation of intracellular organelles, thus understanding the impact of mitochondrial functional changes on overall bone metabolism is crucially important. Recent studies have revealed that mitochondrial homeostasis can lead to morphological and functional abnormalities in senescent cells, particularly in the context of bone diseases. Mitochondrial dysfunction in skeletal diseases results in abnormal metabolism of bone-associated cells and a secondary dysregulated microenvironment within bone tissue. This imbalance in the oxidative system and immune disruption in the bone microenvironment ultimately leads to bone dysplasia. In this review, we examine the latest developments in mitochondrial respiratory chain regulation and its impacts on maintenance of bone health. Specifically, we explored whether enhancing mitochondrial function can reduce the occurrence of bone cell deterioration and improve bone metabolism. These findings offer prospects for developing bone remodeling biology strategies to treat age-related degenerative diseases.
    DOI:  https://doi.org/10.14336/AD.2023.0924
  31. Cell Rep. 2023 Oct 11. pii: S2211-1247(23)01218-4. [Epub ahead of print]42(10): 113206
    ApoE enhances mitochondrial metabolism via microRNA-142a/146a-regulated circuits that suppress hematopoiesis and inflammation in hyperlipidemia.
    Tuan Anh Phu, Ngan K Vu, Martin Ng, Alex S Gao, Joshua S Stoolman, Navdeep S Chandel, Robert L Raffai.
      Apolipoprotein E (ApoE) is recognized for its pleiotropic properties that suppress inflammation. We report that ApoE serves as a metabolic rheostat that regulates microRNA control of glycolytic and mitochondrial activity in myeloid cells and hematopoietic stem and progenitor cells (HSPCs). ApoE expression in myeloid cells increases microRNA-146a, which reduces nuclear factor κB (NF-κB)-driven GLUT1 expression and glycolytic activity. In contrast, ApoE expression reduces microRNA-142a, which increases carnitine palmitoyltransferase 1a (CPT1A) expression, fatty acid oxidation, and oxidative phosphorylation. Improved mitochondrial metabolism by ApoE expression causes an enrichment of tricarboxylic acid (TCA) cycle metabolites and nicotinamide adenine dinucleotide (NAD+) in macrophages. The study of mice with conditional ApoE expression supports the capacity of ApoE to foster microRNA-controlled immunometabolism. Modulation of microRNA-146a and -142a in the hematopoietic system of hyperlipidemic mice using RNA mimics and antagonists, respectively, improves mitochondrial metabolism, which suppresses inflammation and hematopoiesis. Our findings unveil microRNA regulatory circuits, controlled by ApoE, that exert metabolic control over hematopoiesis and inflammation in hyperlipidemia.
    Keywords:  ApoE; CP: Metabolism; CPT1A; Glut1; fatty acid oxidation; hematopoiesis; inflammation; macrophage; microRNA-142a; microRNA-146a; mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2023.113206
  32. J Cardiovasc Pharmacol. 2023 Oct 10.
    The therapeutic potential of targeting ferroptosis in the treatment of mitochondrial cardiomyopathies and heart failure.
    Aubrey C Cantrell, Heng Zeng, Jian-Xiong Chen.
       ABSTRACT: Ferroptosis is a form of iron-regulated cell death implicated in a wide array of diseases, including heart failure, hypertension, and numerous cardiomyopathies. Additionally, mitochondrial dysfunction has been associated with several of these same disease states. However, the role of the mitochondrion in ferroptotic cell death remains debated. As a major regulator of cellular iron levels, the mitochondria may very well play a crucial role in the mechanisms behind ferroptosis, but at this point, this has not been adequately defined. Emerging evidence from our laboratory and others indicates a critical role of mitochondrial Sirtuin 3 (SIRT3), a deacetylase linked with longevity and protection against numerous conditions, in the prevention of cardiovascular diseases. Here, we provide a brief overview of the potential roles of SIRT3 in mitochondrial iron homeostasis, as well as its contribution to the mitochondrial cardiomyopathy of Friedreich's ataxia (FRDA) and diabetic cardiomyopathy (DCM). We also discuss the current knowledge of the involvement of ferroptosis and the mitochondria in these and other cardiovascular disease states, including doxorubicin-induced cardiomyopathy, and provide insight into areas requiring further investigation.
    DOI:  https://doi.org/10.1097/FJC.0000000000001496
  33. Nat Metab. 2023 Oct 09.
    MOF moves into mitochondria.
    Natalie Niemi.
      
    DOI:  https://doi.org/10.1038/s42255-023-00892-x
  34. iScience. 2023 Oct 20. 26(10): 107931
    WTAP boosts lipid oxidation and induces diabetic cardiac fibrosis by enhancing AR methylation.
    Kai Song, He Sun, Bin Tu, Yang Zhou, Li-Chan Lin, Zhi-Yan Liu, Rui Li, Jing-Jing Yang, Ye Zhang, Jian-Yuan Zhao, Hui Tao.
      Dysregulated lipid metabolism occurs in pathological processes characterized by cell proliferation and migration. Nonetheless, the mechanism of increased mitochondrial lipid oxidation is poorly appreciated in diabetic cardiac fibrosis, which is accompanied by enhanced fibroblast proliferation and migration. Herein, increased WTAP expression promotes cardiac fibroblast proliferation and migration, contributing to diabetic cardiac fibrosis. Knockdown of WTAP suppresses mitochondrial lipid oxidation, fibroblast proliferation and migration to ameliorate diabetic cardiac fibrosis. Mechanistically, WTAP-mediated m6A methylation of AR induced its degradation, dependent on YTHDF2. Additionally, AR directly interacts with mitochondrial lipid oxidation enzyme Decr1; overexpression of AR-suppressed Decr1-mediates mitochondrial lipid oxidation, inhibiting cardiac fibroblast proliferation and migration. Knockdown of AR produced the opposite effect. Clinically, increased WTAP and YTHDF2 levels correlate with decreased AR expression in human DCM heart tissue. We describe a mechanism wherein WTAP boosts higher mitochondrial lipid oxidation, cardiac fibroblast proliferation, and migration by enhancing AR methylation in a YTHDF2-dependent manner.
    Keywords:  Biological sciences; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.107931
  35. JCI Insight. 2023 Oct 10. pii: e171772. [Epub ahead of print]
    GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle.
    George R Marcotte, Matthew J Miller, Hawley E Kunz, Zachary C Ryan, Matthew D Strub, Patrick M Vanderboom, Carrie J Heppelmann, Sarah Chau, Zachary D Von Ruff, Sean P Kilroe, Andrew T McKeen, Jason M Dierdorff, Jennifer I Stern, Karl A Nath, Chad E Grueter, Vitor A Lira, Andrew R Judge, Blake B Rasmussen, K Sreekumaran Nair, Ian R Lanza, Scott M Ebert, Christopher M Adams.
      Aging and many illnesses and injuries impair skeletal muscle mass and function, but the molecular mechanisms are not well understood. To better understand the mechanisms, we generated and studied transgenic mice with skeletal muscle-specific expression of Growth Arrest and DNA Damage Inducible Alpha (GADD45A), a signaling protein whose expression in skeletal muscle rises during aging and a wide range of illnesses and injuries. We found that GADD45A induced several cellular changes that are characteristic of skeletal muscle atrophy, including a reduction in skeletal muscle mitochondria and oxidative capacity, selective atrophy of glycolytic muscle fibers, and paradoxical expression of oxidative myosin heavy chains despite mitochondrial loss. These cellular changes were at least partly mediated by MEKK4, a protein kinase that is directly activated by GADD45A. By inducing these changes, GADD45A decreased the mass of muscles that are enriched in glycolytic fibers, and it impaired strength, specific force, and endurance exercise capacity. Furthermore, as predicted by data from mouse models, we found that GADD45A expression in skeletal muscle was associated with muscle weakness in humans. Collectively, these findings identify GADD45A as a mediator of mitochondrial loss, atrophy, and weakness in mouse skeletal muscle and a potential target for muscle weakness in humans.
    Keywords:  Metabolism; Mitochondria; Muscle Biology; Skeletal muscle
    DOI:  https://doi.org/10.1172/jci.insight.171772
  36. Trends Endocrinol Metab. 2023 Oct 05. pii: S1043-2760(23)00197-2. [Epub ahead of print]
    Brain mitochondria in behavior: more than a powerhouse.
    Alexia Crockett, Fiona Hollis.
      Rosenberg and colleagues developed a miniaturized assay of mitochondrial content and energy transformation capacity that allowed them to assess mitochondrial features and activities across the brain in male mice. Their findings provide a comprehensive brain-wide map of mitochondrial associations with stress-induced behaviors and highlight mitochondria as dynamic, spatially-organized organelles.
    Keywords:  behavior; brain bioenergetics; mitochondria; stress
    DOI:  https://doi.org/10.1016/j.tem.2023.09.008
  37. Int J Mol Sci. 2023 Sep 25. pii: 14507. [Epub ahead of print]24(19):
    Vanadium Pentoxide Exposure Causes Strain-Dependent Changes in Mitochondrial DNA Heteroplasmy, Copy Number, and Lesions, but Not Nuclear DNA Lesions.
    Nick L Dobson, Steven R Kleeberger, Adam B Burkholder, Dianne M Walters, Wesley Gladwell, Kevin Gerrish, Heather L Vellers.
      Interstitial lung diseases (ILDs) are lethal lung diseases characterized by pulmonary inflammation and progressive lung interstitial scarring. We previously developed a mouse model of ILD using vanadium pentoxide (V2O5) and identified several gene candidates on chromosome 4 associated with pulmonary fibrosis. While these data indicated a significant genetic contribution to ILD susceptibility, they did not include any potential associations and interactions with the mitochondrial genome that might influence disease risk. To conduct this pilot work, we selected the two divergent strains we previously categorized as V2O5-resistant C57BL6J (B6) and -responsive DBA/2J (D2) and compared their mitochondrial genome characteristics, including DNA variants, heteroplasmy, lesions, and copy numbers at 14- and 112-days post-exposure. While we did not find changes in the mitochondrial genome at 14 days post-exposure, at 112 days, we found that the responsive D2 strain exhibited significantly fewer mtDNA copies and more lesions than control animals. Alongside these findings, mtDNA heteroplasmy frequency decreased. These data suggest that mice previously shown to exhibit increased susceptibility to pulmonary fibrosis and inflammation sustain damage to the mitochondrial genome that is evident at 112 days post-V2O5 exposure.
    Keywords:  heteroplasmy; mitochondrial sequencing; mtDNA copy number; mtDNA damage; vanadium pentoxide
    DOI:  https://doi.org/10.3390/ijms241914507
  38. Elife. 2023 Oct 11. pii: e86452. [Epub ahead of print]12
    GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes.
    Jayashree Jena, Luis Miguel García-Peña, Eric T Weatherford, Alex Marti, Sarah H Bjorkman, Kevin Kato, Jivan Koneru, Jason H Chen, Randy J Seeley, E Dale Abel, Renata O Pereira.
      We previously reported that mice lacking the protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) display induction of the activating transcription factor 4 (ATF4), which promotes fibroblast growth factor 21 (FGF21) secretion as a batokine. FGF21 increases metabolic rates under baseline conditions but is dispensable for the resistance to diet-induced obesity (DIO) reported in OPA1 BKO mice (Pereira et al., 2021). To determine alternative mediators of this phenotype, we performed transcriptome analysis, which revealed increased levels of growth differentiation factor 15 (GDF15), along with increased protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) levels in BAT. To investigate whether ATF4 induction was mediated by PERK and evaluate the contribution of GDF15 to the resistance to DIO, we selectively deleted PERK or GDF15 in OPA1 BKO mice. Mice with reduced OPA1 and PERK levels in BAT had preserved ISR activation. Importantly, simultaneous deletion of OPA1 and GDF15 partially reversed the resistance to DIO and abrogated the improvements in glucose tolerance. Furthermore, GDF15 was required to improve cold-induced thermogenesis in OPA1 BKO mice. Taken together, our data indicate that PERK is dispensable to induce the ISR, but GDF15 contributes to the resistance to DIO, and is required for glucose homeostasis and thermoregulation in OPA1 BKO mice by increasing energy expenditure.
    Keywords:  GDF15; PERK; biochemistry; brown adipose tissue; chemical biology; integrated stress response; mitochondrial stress; mouse
    DOI:  https://doi.org/10.7554/eLife.86452
  39. Eur J Endocrinol. 2023 Oct 10. pii: lvad137. [Epub ahead of print]
    Adrenocortical function in patients with Single Large Scale Mitochondrial DNA Deletions: a retrospective single centre cohort study.
    Barbara Siri, Annamaria D'Alessandro, Arianna Maiorana, Ottavia Porzio, Lucilla Ravà, Carlo Dionisi-Vici, Marco Cappa, Diego Martinelli.
       OBJECTIVE: Single Large Scale Mitochondrial DNA Deletions (SLSMDs), Pearson Syndrome (PS) and Kearns-Sayre Syndrome (KSS), are systemic diseases with multiple endocrine abnormalities. The adrenocortical function has not been systematically investigated with a few anecdotal reports of overt adrenal insufficiency (AI). The study aimed to assess the adrenocortical function in a large cohort of SLSMDs.
    DESIGN AND METHODS: A retrospective monocentric longitudinal study involved a cohort of 18 SLSMDs patients. Adrenocortical function was evaluated by baseline adrenocorticotrophic hormone (ACTH) and cortisol measurements and by high- (HDT) and low-dose (LDT) ACTH stimulation tests and compared with 92 healthy controls (HC).
    RESULTS: Baseline adrenocortical function was impaired in 39% of patients and by the end of the study 66% of PS and 25% of KSS showed an insufficient increase after ACTH stimulation, with cortisol deficiency due to primary AI in most PS and subclinical AI in KSS. Symptomatic AI was recorded in 44% of patients.Peak cortisol levels after ACTH stimulation tests were significantly lower in patients than in HC (p<0.0001), with a more reduced response to LDT vs HDT (p<0.05).
    CONCLUSIONS: Our study highlights that cortisol deficiency due to primary AI represents a relevant part of the clinical spectrum in SLSMDs, with more severe impairment in PS than in KSS. Basal and after-stimulus assessment of adrenocortical axis should be early and regularly investigated to identify any degree of adrenocortical dysfunction. The study allowed the elaboration of a diagnostic process designed for the diagnosis, treatment, and follow-up of adrenocortical abnormalities in SLSMDs.
    Keywords:  ACTH stimulation tests; Single large scale mtDNA deletions; glucocorticoid replacement therapy; primary adrenal insufficiency
    DOI:  https://doi.org/10.1093/ejendo/lvad137
  40. Int J Mol Sci. 2023 Sep 22. pii: 14421. [Epub ahead of print]24(19):
    Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration.
    Hariprasath Ragupathy, Manasvi Vukku, Sandeep Kumar Barodia.
      Neurodegeneration is an age-dependent progressive phenomenon with no defined cause. Aging is the main risk factor for neurodegenerative diseases. During aging, activated microglia undergo phenotypic alterations that can lead to neuroinflammation, which is a well-accepted event in the pathogenesis of neurodegenerative diseases. Several common mechanisms are shared by genetically or pathologically distinct neurodegenerative diseases, such as excitotoxicity, mitochondrial deficits and oxidative stress, protein misfolding and translational dysfunction, autophagy and microglia activation. Progressive loss of the neuronal population due to increased oxidative stress leads to neurodegenerative diseases, mostly due to the accumulation of dysfunctional mitochondria. Mitochondrial dysfunction and excessive neuroinflammatory responses are both sufficient to induce pathology in age-dependent neurodegeneration. Therefore, mitochondrial quality control is a key determinant for the health and survival of neuronal cells in the brain. Research has been primarily focused to demonstrate the significance of neuronal mitochondrial health, despite the important contributions of non-neuronal cells that constitute a significant portion of the brain volume. Moreover, mitochondrial morphology and function are distinctly diverse in different tissues; however, little is known about their molecular diversity among cell types. Mitochondrial dynamics and quality in different cell types markedly decide the fate of overall brain health; therefore, it is not justifiable to overlook non-neuronal cells and their significant and active contribution in facilitating overall neuronal health. In this review article, we aim to discuss the mitochondrial quality control of different cell types in the brain and how important and remarkable the diversity and highly synchronized connecting property of non-neuronal cells are in keeping the neurons healthy to control neurodegeneration.
    Keywords:  astrocytes; microglia; mitochondria; neurons; oligodendrocytes; oxidative stress
    DOI:  https://doi.org/10.3390/ijms241914421
  41. Genetica. 2023 Oct 11.
    The misregulation of mitochondria-associated genes caused by GAGA-factor lack promotes autophagic germ cell death in Drosophila testes.
    Natalia V Dorogova, Svetlana A Fedorova, Elena U Bolobolova, Elina M Baricheva.
      The Drosophila GAGA-factor encoded by the Trithorax-like (Trl) gene is DNA-binding protein with unusually wide range of applications in diverse cell contexts. In Drosophila spermatogenesis, reduced GAGA expression caused by Trl mutations induces mass autophagy leading to germ cell death. In this work, we investigated the contribution of mitochondrial abnormalities to autophagic germ cell death in Trl gene mutants. Using a cytological approach, in combination with an analysis of high-throughput RNA sequencing (RNA-seq) data, we demonstrated that the GAGA deficiency led to considerable defects in mitochondrial ultrastructure, by causing misregulation of GAGA target genes encoding essential components of mitochondrial molecular machinery. Mitochondrial anomalies induced excessive production of reactive oxygen species and their release into the cytoplasm, thereby provoking oxidative stress. Changes in transcription levels of some GAGA-independent genes in the Trl mutants indicated that testis cells experience ATP deficiency and metabolic aberrations, that may trigger extensive autophagy progressing to cell death.
    Keywords:  Autophagic cell death; Drosophila; GAGA-factor; Mitochondria; Spermatogenesis
    DOI:  https://doi.org/10.1007/s10709-023-00197-7
  42. PLoS Genet. 2023 Oct;19(10): e1010972
    Constructing and interpreting a large-scale variant effect map for an ultrarare disease gene: Comprehensive prediction of the functional impact of PSAT1 genotypes.
    Michael J Xie, Gareth A Cromie, Katherine Owens, Martin S Timour, Michelle Tang, J Nathan Kutz, Ayman W El-Hattab, Richard N McLaughlin, Aimée M Dudley.
      Reduced activity of the enzymes encoded by PHGDH, PSAT1, and PSPH causes a set of ultrarare, autosomal recessive diseases known as serine biosynthesis defects. These diseases present in a broad phenotypic spectrum: at the severe end is Neu-Laxova syndrome, in the intermediate range are infantile serine biosynthesis defects with severe neurological manifestations and growth deficiency, and at the mild end is childhood disease with intellectual disability. However, L-serine supplementation, especially if started early, can ameliorate and in some cases even prevent symptoms. Therefore, knowledge of pathogenic variants can improve clinical outcomes. Here, we use a yeast-based assay to individually measure the functional impact of 1,914 SNV-accessible amino acid substitutions in PSAT. Results of our assay agree well with clinical interpretations and protein structure-function relationships, supporting the inclusion of our data as functional evidence as part of the ACMG variant interpretation guidelines. We use existing ClinVar variants, disease alleles reported in the literature and variants present as homozygotes in the primAD database to define assay ranges that could aid clinical variant interpretation for up to 98% of the tested variants. In addition to measuring the functional impact of individual variants in yeast haploid cells, we also assay pairwise combinations of PSAT1 alleles that recapitulate human genotypes, including compound heterozygotes, in yeast diploids. Results from our diploid assay successfully distinguish the genotypes of affected individuals from those of healthy carriers and agree well with disease severity. Finally, we present a linear model that uses individual allele measurements to predict the biallelic function of ~1.8 million allele combinations corresponding to potential human genotypes. Taken together, our work provides an example of how large-scale functional assays in model systems can be powerfully applied to the study of ultrarare diseases.
    DOI:  https://doi.org/10.1371/journal.pgen.1010972
  43. bioRxiv. 2023 Sep 30. pii: 2023.09.30.560315. [Epub ahead of print]
    Forward genetic screens identify mechanisms of resistance to small molecule lactate dehydrogenase inhibitors.
    Anderson R Frank, Florentina Vandiver, David G McFadden.
      Altered metabolism is a hallmark of cancer; however, it has been difficult to specifically target metabolism in cancer for therapeutic benefit. Cancers with genetically defined defects in metabolic enzymes constitute a subset of cancers where targeting metabolism is potentially accessible. Hürthle cell carcinoma of the thyroid (HTC) tumors frequently harbor deleterious mitochondrial DNA (mtDNA) mutations in subunits of complex I of the mitochondrial electron transport chain (ETC). Previous work has shown that HTC models with deleterious mtDNA mutations exhibit mitochondrial ETC defects that expose lactate dehydrogenase (LDH) as a therapeutic vulnerability. Here, we performed forward genetic screens to identify mechanisms of resistance to small molecule LDH inhibitors. We identified two distinct mechanisms of resistance: upregulation of an LDH isoform and a compound-specific resistance mutation. Using these tools, we demonstrate that the anti-cancer activity of LDH inhibitors in cell line and xenograft models of complex I-mutant HTC is through on-target LDH inhibition.
    DOI:  https://doi.org/10.1101/2023.09.30.560315
  44. Front Genet. 2023 ;14 1264899
    Next-generation sequencing improves precision medicine in hearing loss.
    T Imizcoz, C Prieto-Matos, R Manrique-Huarte, D Calavia, A Huarte, P C Pruneda, G R Ordoñez, E Cañada-Higueras, A Patiño-García, G Alkorta-Aranburu, M Manrique Rodríguez.
      Background: An early etiological diagnosis of hearing loss positively impacts children's quality of life including language and cognitive development. Even though hearing loss associates with extremely high genetic and allelic heterogeneity, several studies have proven that Next-Generation Sequencing (NGS)-based gene panel testing significantly reduces the time between onset and diagnosis. Methods: In order to assess the clinical utility of our custom NGS GHELP panel, the prevalence of pathogenic single nucleotide variants, indels or copy number variants was assessed by sequencing 171 nuclear and 8 mitochondrial genes in 155 Spanish individuals with hearing loss. Results: A genetic diagnosis of hearing loss was achieved in 34% (52/155) of the individuals (5 out of 52 were syndromic). Among the diagnosed cases, 87% (45/52) and 12% (6/52) associated with autosomal recessive and dominant inheritance patterns respectively; remarkably, 2% (1/52) associated with mitochondrial inheritance pattern. Although the most frequently mutated genes in this cohort were consistent with those described in the literature (GJB2, OTOF or MYO7A), causative variants in less frequent genes such as TMC1, FGF3 or mitCOX1 were also identified. Moreover, 5% of the diagnosed cases (3/52) were associated with pathogenic copy number variants. Conclusion: The clinical utility of NGS panels that allows identification of different types of pathogenic variants-not only single nucleotide variants/indels in both nuclear and mitochondrial genes but also copy number variants-has been demonstrated to reduce the clinical diagnostic odyssey in hearing loss. Thus, clinical implementation of genomic strategies within the regular clinical practice, and, more significantly, within the newborn screening protocols, is warranted.
    Keywords:  NGS; diagnosis; gene panel; hearing loss; precision medicine
    DOI:  https://doi.org/10.3389/fgene.2023.1264899
  45. Aging Cell. 2023 Oct 13. e14000
    Carnitine acetyltransferase deficiency mediates mitochondrial dysfunction-induced cellular senescence in dermal fibroblasts.
    Min Ji Song, Chi-Hyun Park, Haesoo Kim, Sangbum Han, Si Hyung Lee, Dong Hun Lee, Jin Ho Chung.
      Aging is accompanied by impaired mitochondrial function and accumulation of senescent cells. Mitochondrial dysfunction contributes to senescence by increasing the levels of reactive oxygen species and compromising energy metabolism. Senescent cells secrete a senescence-associated secretory phenotype (SASP) and stimulate chronic low-grade inflammation, ultimately inducing inflammaging. Mitochondrial dysfunction and cellular senescence are two closely related hallmarks of aging; however, the key driver genes that link mitochondrial dysfunction and cellular senescence remain unclear. Here, we aimed to elucidate a novel role of carnitine acetyltransferase (CRAT) in the development of mitochondrial dysfunction and cellular senescence in dermal fibroblasts. Transcriptomic analysis of skin tissues from young and aged participants showed significantly decreased CRAT expression in intrinsically aged skin. CRAT downregulation in human dermal fibroblasts recapitulated mitochondrial changes in senescent cells and induced SASP secretion. Specifically, CRAT knockdown caused mitochondrial dysfunction, as indicated by increased oxidative stress, disruption of mitochondrial morphology, and a metabolic shift from oxidative phosphorylation to glycolysis. Mitochondrial damage induced the release of mitochondrial DNA into the cytosol, which activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NF-ĸB pathways to induce SASPs. Consistently, fibroblast-specific CRAT-knockout mice showed increased skin aging phenotypes in vivo, including decreased cell proliferation, increased SASP expression, increased inflammation, and decreased collagen density. Our results suggest that CRAT deficiency contributes to aging by mediating mitochondrial dysfunction-induced senescence.
    Keywords:  carnitine acetyltransferase; cellular senescence; mitochondrial dysfunction; oxidative stress; skin aging
    DOI:  https://doi.org/10.1111/acel.14000
  46. Nat Rev Genet. 2023 Oct 11.
    Predicting variant pathogenicity with AlphaMissense.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41576-023-00668-9
  47. Nat Commun. 2023 Oct 12. 14(1): 6403
    Simulation of undiagnosed patients with novel genetic conditions.
    Undiagnosed Diseases Network
      Rare Mendelian disorders pose a major diagnostic challenge and collectively affect 300-400 million patients worldwide. Many automated tools aim to uncover causal genes in patients with suspected genetic disorders, but evaluation of these tools is limited due to the lack of comprehensive benchmark datasets that include previously unpublished conditions. Here, we present a computational pipeline that simulates realistic clinical datasets to address this deficit. Our framework jointly simulates complex phenotypes and challenging candidate genes and produces patients with novel genetic conditions. We demonstrate the similarity of our simulated patients to real patients from the Undiagnosed Diseases Network and evaluate common gene prioritization methods on the simulated cohort. These prioritization methods recover known gene-disease associations but perform poorly on diagnosing patients with novel genetic disorders. Our publicly-available dataset and codebase can be utilized by medical genetics researchers to evaluate, compare, and improve tools that aid in the diagnostic process.
    DOI:  https://doi.org/10.1038/s41467-023-41980-6
  48. bioRxiv. 2023 Sep 27. pii: 2023.09.26.559521. [Epub ahead of print]
    Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition.
    University of Washington Center for Mendelian Genomics (UW-CMG)
      Resolving the molecular basis of a Mendelian condition (MC) remains challenging owing to the diverse mechanisms by which genetic variants cause disease. To address this, we developed a synchronized long-read genome, methylome, epigenome, and transcriptome sequencing approach, which enables accurate single-nucleotide, insertion-deletion, and structural variant calling and diploid de novo genome assembly, and permits the simultaneous elucidation of haplotype-resolved CpG methylation, chromatin accessibility, and full-length transcript information in a single long-read sequencing run. Application of this approach to an Undiagnosed Diseases Network (UDN) participant with a chromosome X;13 balanced translocation of uncertain significance revealed that this translocation disrupted the functioning of four separate genes ( NBEA , PDK3 , MAB21L1 , and RB1 ) previously associated with single-gene MCs. Notably, the function of each gene was disrupted via a distinct mechanism that required integration of the four 'omes' to resolve. These included nonsense-mediated decay, fusion transcript formation, enhancer adoption, transcriptional readthrough silencing, and inappropriate X chromosome inactivation of autosomal genes. Overall, this highlights the utility of synchronized long-read multi-omic profiling for mechanistically resolving complex phenotypes.
    DOI:  https://doi.org/10.1101/2023.09.26.559521
  49. J Biol Chem. 2023 Oct 10. pii: S0021-9258(23)02361-X. [Epub ahead of print] 105333
    Reactive nitrogen species inhibit branched chain alpha-ketoacid dehydrogenase complex and impact muscle cell metabolism.
    Nicholas L Arp, Gretchen L Seim, James A Votava, Jordyn Josephson, Jing Fan.
      Branched chain α-ketoacid dehydrogenase complex (BCKDC) is the rate-limiting enzyme in branched chain amino acid (BCAA) catabolism, a metabolic pathway with great importance for human health. BCKDC belongs to the mitochondrial α-ketoacid dehydrogenase complex family, which also includes pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC). Here we revealed that BCKDC can be substantially inhibited by reactive nitrogen species (RNS) via a mechanism similar to what we recently discovered with PDHC and OGDC - RNS can cause inactivating covalent modifications of the lipoic arm on its E2 subunit. In addition, we showed that such reaction between RNS and the lipoic arm of the E2 subunit can further promote inhibition of the E3 subunits of α-ketoacid dehydrogenase complexes. We examined the impacts of this RNS-mediated BCKDC inhibition in muscle cells, an important site of BCAA metabolism, and demonstrated that the nitric oxide production induced by cytokine stimulation leads to a strong inhibition of BCKDC activity and BCAA oxidation in myotubes and myoblasts. More broadly, nitric oxide production reduced the level of functional lipoic arms across the multiple α-ketoacid dehydrogenases and led to intracellular accumulation of their substrates (α-ketoacids), decrease of their products (acyl-CoAs), and a lower cellular energy charge. In sum, this work revealed a new mechanism for BCKDC regulation, demonstrated that RNS can generally inhibit all α-ketoacid dehydrogenases, which has broad physiological implications across multiple cell types, and elucidated the mechanistic connection between RNS-driven inhibitory modifications on the E2 and E3 subunits of α-ketoacid dehydrogenases.
    Keywords:  branched chain amino acid; metabolic regulation; mitochondria metabolism; nitric oxide; α-ketoacid dehydrogenase
    DOI:  https://doi.org/10.1016/j.jbc.2023.105333
  50. Cells. 2023 Oct 03. pii: 2397. [Epub ahead of print]12(19):
    Mitochondrial Dysfunction and Decreased Cytochrome c in Cell and Animal Models of Machado-Joseph Disease.
    Filipa Almeida, Ildete L Ferreira, Luana Naia, Daniela Marinho, Ana Catarina Vilaça-Ferreira, Marta D Costa, Sara Duarte-Silva, Patrícia Maciel, A Cristina Rego.
      Mitochondrial dysfunction has been described in many neurodegenerative disorders; however, there is less information regarding mitochondrial deficits in Machado-Joseph disease (MJD), a polyglutamine (polyQ) disorder caused by CAG repeat expansion in the ATXN3 gene. In the present study, we characterized the changes in mitochondrial function and biogenesis markers in two MJD models, CMVMJD135 (MJD135) transgenic mice at a fully established phenotype stage and tetracycline-regulated PC6-3 Q108 cell line expressing mutant ataxin-3 (mATXN3). We detected mATXN3 in the mitochondrial fractions of PC6-3 Q108 cells, suggesting the interaction of expanded ATXN3 with the organelle. Interestingly, in both the cerebella of the MJD135 mouse model and in PC6-3 Q108 cells, we found decreased mitochondrial respiration, ATP production and mitochondrial membrane potential, strongly suggesting mitochondrial dysfunction in MJD. Also, in PC6-3 Q108 cells, an additional enhanced glycolytic flux was observed. Supporting the functional deficits observed in MJD mitochondria, MJD135 mouse cerebellum and PC6-3 Q108 cells showed reduced cytochrome c mRNA and protein levels. Overall, our findings show compromised mitochondrial function associated with decreased cytochrome c levels in both cell and animal models of MJD.
    Keywords:  Machado–Joseph disease; calcium handling; mitochondrial membrane potential; mitochondrial transcription; oxygen consumption
    DOI:  https://doi.org/10.3390/cells12192397
  51. Science. 2023 Oct 13. 382(6667): eadf7044
    A comparative atlas of single-cell chromatin accessibility in the human brain.
    Yang Eric Li, Sebastian Preissl, Michael Miller, Nicholas D Johnson, Zihan Wang, Henry Jiao, Chenxu Zhu, Zhaoning Wang, Yang Xie, Olivier Poirion, Colin Kern, Antonio Pinto-Duarte, Wei Tian, Kimberly Siletti, Nora Emerson, Julia Osteen, Jacinta Lucero, Lin Lin, Qian Yang, Quan Zhu, Nathan Zemke, Sarah Espinoza, Anna Marie Yanny, Julie Nyhus, Nick Dee, Tamara Casper, Nadiya Shapovalova, Daniel Hirschstein, Rebecca D Hodge, Sten Linnarsson, Trygve Bakken, Boaz Levi, C Dirk Keene, Jingbo Shang, Ed Lein, Allen Wang, M Margarita Behrens, Joseph R Ecker, Bing Ren.
      Recent advances in single-cell transcriptomics have illuminated the diverse neuronal and glial cell types within the human brain. However, the regulatory programs governing cell identity and function remain unclear. Using a single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq), we explored open chromatin landscapes across 1.1 million cells in 42 brain regions from three adults. Integrating this data unveiled 107 distinct cell types and their specific utilization of 544,735 candidate cis-regulatory DNA elements (cCREs) in the human genome. Nearly a third of the cCREs demonstrated conservation and chromatin accessibility in the mouse brain cells. We reveal strong links between specific brain cell types and neuropsychiatric disorders including schizophrenia, bipolar disorder, Alzheimer's disease (AD), and major depression, and have developed deep learning models to predict the regulatory roles of noncoding risk variants in these disorders.
    DOI:  https://doi.org/10.1126/science.adf7044
  52. Nature. 2023 Oct 11.
    Structures illustrate step-by-step mitochondrial transcription initiation.
    Quinten Goovaerts, Jiayu Shen, Brent De Wijngaert, Urmimala Basu, Smita S Patel, Kalyan Das.
      Transcription initiation is a key regulatory step in gene expression during which RNA polymerase (RNAP) initiates RNA synthesis de novo, and the synthesized RNA at a specific length triggers the transition to the elongation phase. Mitochondria recruit a single-subunit RNAP and one or two auxiliary factors to initiate transcription. Previous studies have revealed the molecular architectures of yeast1 and human2 mitochondrial RNAP initiation complexes (ICs). Here we provide a comprehensive, stepwise mechanism of transcription initiation by solving high-resolution cryogenic electron microscopy (cryo-EM) structures of yeast mitochondrial RNAP and the transcription factor Mtf1 catalysing two- to eight-nucleotide RNA synthesis at single-nucleotide addition steps. The growing RNA-DNA is accommodated in the polymerase cleft by template scrunching and non-template reorganization, creating stressed intermediates. During early initiation, non-template strand scrunching and unscrunching destabilize the short two- and three-nucleotide RNAs, triggering abortive synthesis. Subsequently, the non-template reorganizes into a base-stacked staircase-like structure supporting processive five- to eight-nucleotide RNA synthesis. The expanded non-template staircase and highly scrunched template in IC8 destabilize the promoter interactions with Mtf1 to facilitate initiation bubble collapse and promoter escape for the transition from initiation to the elongation complex (EC). The series of transcription initiation steps, each guided by the interplay of multiple structural components, reveal a finely tuned mechanism for potential regulatory control.
    DOI:  https://doi.org/10.1038/s41586-023-06643-y
  53. Exp Hematol. 2023 Oct 11. pii: S0301-472X(23)01736-8. [Epub ahead of print]
    The multifaceted role of mitochondria in HSC fate decisions: energy and beyond.
    Marie-Dominique Filippi.
      Hematopoietic stem cells (HSCs) have the properties to self-renew and/or differentiate into all mature blood cell lineages. The fate decisions to generate progeny that retain stemness properties or that commit to differentiation is a fundamental process to maintain tissue homeostasis and must be tightly regulated in order to prevent HSC overgrowth or exhaustion. HSC fate decisions are inherently coupled to cell division. The transition from quiescence to activation is accompanied by major metabolic and mitochondrial changes that are important for cell cycle entry for balanced decisions between self-renewal and differentiation. In this review, we discuss the current understanding of the role of mitochondrial metabolism in HSC transition from quiescence to activation and fate decisions.
    DOI:  https://doi.org/10.1016/j.exphem.2023.10.001
  54. Curr Protoc. 2023 Oct;3(10): e906
    Facilitating the Molecular Diagnosis of Rare Genetic Disorders Through Facial Phenotypic Scores.
    Tzung-Chien Hsieh, Hellen Lesmann, Peter M Krawitz.
      With recent advances in computer vision, many applications based on artificial intelligence have been developed to facilitate the diagnosis of rare genetic disorders through the analysis of patients' two-dimensional frontal images. Some of these have been implemented on online platforms with user-friendly interfaces and provide facial analysis services, such as Face2Gene. However, users cannot run the facial analysis processes in house because the training data and the trained models are unavailable. This article therefore provides an introduction, designed for users with programming backgrounds, to the use of the open-source GestaltMatcher approach to run facial analysis in their local environment. The Basic Protocol provides detailed instructions for applying for access to the trained models and then performing facial analysis to obtain a prediction score for each of the 595 genes in the GestaltMatcher Database. The prediction results can then be used to narrow down the search space of disease-causing mutations or further connect with a variant-prioritization pipeline. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Using the open-source GestaltMatcher approach to perform facial analysis.
    Keywords:  facial dysmorphism; facial phenotyping; next-generation phenotyping; rare disorders; variants prioritization
    DOI:  https://doi.org/10.1002/cpz1.906
  55. Nat Biotechnol. 2023 Oct;41(10): 1386
    Monitoring protein proximity with fluorogens.
    Alexandra Despang.
      
    DOI:  https://doi.org/10.1038/s41587-023-02000-6
  56. J Community Genet. 2023 Oct 10.
    A feasible molecular diagnostic strategy for rare genetic disorders within resource-constrained environments.
    Maria Mabyalwa Mudau, Heather Seymour, Patracia Nevondwe, Robyn Kerr, Careni Spencer, Candice Feben, Zané Lombard, Engela Honey, Amanda Krause, Nadia Carstens.
      Timely and accurate diagnosis of rare genetic disorders is critical, as it enables improved patient management and prognosis. In a resource-constrained environment such as the South African State healthcare system, the challenge is to design appropriate and cost-effective assays that will enable accurate genetic diagnostic services in patients of African ancestry across a broad disease spectrum. Next-generation sequencing (NGS) has transformed testing approaches for many Mendelian disorders, but this technology is still relatively new in our setting and requires cost-effective ways to implement. As a proof of concept, we describe a feasible diagnostic strategy for genetic disorders frequently seen in our genetics clinics (RASopathies, Cornelia de Lange syndrome, Treacher Collins syndrome, and CHARGE syndrome). The custom-designed targeted NGS gene panel enabled concurrent variant screening for these disorders. Samples were batched during sequencing and analyzed selectively based on the clinical phenotype. The strategy employed in the current study was cost-effective, with sequencing and analysis done at USD849.68 per sample and achieving an overall detection rate of 54.5%. The strategy employed is cost-effective as it allows batching of samples from patients with different diseases in a single run, an approach that can be utilized with rare and less frequently ordered molecular diagnostic tests. The subsequent selective analysis pipeline allowed for timeous reporting back of patients results. This is feasible with a reasonable yield and can be employed for the molecular diagnosis of a wide range of rare monogenic disorders in a resource-constrained environment.
    Keywords:  Custom-designed NGS targeted panel; Genetic testing; Rare diseases; Resource-constrained environment
    DOI:  https://doi.org/10.1007/s12687-023-00674-8
  57. Biomed Pharmacother. 2023 Oct 07. pii: S0753-3322(23)01449-X. [Epub ahead of print]168 115651
    Allogeneic mitochondrial transplantation ameliorates cardiac dysfunction due to doxorubicin: An in vivo study.
    Farshid Maleki, Shahram Rabbani, Reza Shirkoohi, Mohsen Rezaei.
      Damage to the mitochondria may lead to serious conditions that are difficult to treat. Doxorubicin is one of the most widely used chemotherapeutic drugs for the treatment of malignancies in children and adults, and reportedly causes damage to the mitochondria. Unfortunately, the dangerous cardiac side effects of doxorubicin appear when the patient is in the midst of a vigorous fight against the disease, either by taking doxorubicin alone or in combination with other drugs. This study aimed to determine whether exogenous healthy and functional mitochondria are internalized by cells, can it help the survival of these cells, and can reduce cardiotoxicity. For this purpose, isolated, pure, and functional exogenous mitochondria were injected into the tail vein of a rat model of doxorubicin-induced cardiotoxicity. After that, the heart function of the rats and their antioxidant status, inflammatory markers, and histopathological examination were investigated. Our findings show that intravenous mitochondrial transplantation provided efficient mitochondrial uptake and reduced cardiotoxicity by reducing ROS production, lipid peroxidation, and inflammation. In addition, the levels of ATP and antioxidant enzymes increased after mitochondrial transplantation; therefore all of these complex processes resulted in the reduction of apoptosis and necrosis in rat heart tissue. These promising results open the way to more effective cancer treatment without the side effects of related drugs. Transplanting exogenous mitochondria probably enhances the cell's mitochondrial network, potentially treating mitochondria-related disorders such as cardiovascular and neurodegenerative diseases, although the exact relationship between mitochondrial damage and these conditions remains unclear.
    Keywords:  Cardiotoxicity; Chemotherapy; Doxorubicin; Mitochondrial transplantation; Oxidative stress
    DOI:  https://doi.org/10.1016/j.biopha.2023.115651
  58. J Med Genet. 2023 Oct 13. pii: jmg-2023-109504. [Epub ahead of print]
    Intellectual disability syndrome associated with a homozygous founder variant in SGSM3 in Ashkenazi Jews.
    Rivka Birnbaum, Shlomit Ezer, Nava Shaul Lotan, Avital Eilat, Keren Sternlicht, Lilach Benyamini, Orit Reish, Tzipora Falik-Zaccai, Gali Ben-Gad, Raya Rod, Reeval Segel, Katherine Kim, Barabra Burton, Catherine E Keegan, Mallory Wagner, Lindsay B Henderson, Nofar Mor, Ortal Barel, Yoel Hirsch, Vardiella Meiner, Orly Elpeleg, Tamar Harel, Hagar Mor-Shakad.
       BACKGROUND: Neurodevelopmental disorders (NDDs) impact both the development and functioning of the brain and exhibit clinical and genetic variability. RAP and RAB proteins, belonging to the RAS superfamily, are identified as established contributors to NDDs. However, the involvement of SGSM (small G protein signalling modulator), another member of the RAS family, in NDDs has not been previously documented.
    METHODS: Proband-only or trio exome sequencing was performed on DNA samples obtained from affected individuals and available family members. The variant prioritisation process focused on identifying rare deleterious variants. International collaboration aided in the identification of additional affected individuals.
    RESULTS: We identified 13 patients from 8 families of Ashkenazi Jewish origin who all carried the same homozygous frameshift variant in SGSM3 gene. The variant was predicted to cause a loss of function, potentially leading to impaired protein structure or function. The variant co-segregated with the disease in all available family members. The affected individuals displayed mild global developmental delay and mild to moderate intellectual disability. Additional prevalent phenotypes observed included hypotonia, behavioural challenges and short stature.
    CONCLUSIONS: An Ashkenazi Jewish homozygous founder variant in SGSM3 was discovered in individuals with NDDs and short stature. This finding establishes a connection between another member of the RAS family and NDDs. Additional research is needed to uncover the specific molecular mechanisms by which SGSM3 influences neurodevelopmental processes and the regulation of growth.
    Keywords:  Genetic Research; Genetic Variation; Human Genetics
    DOI:  https://doi.org/10.1136/jmg-2023-109504
  59. JAMA Cardiol. 2023 Oct 11.
    Mitochondrial Respiration and Exercise Performance in Patients With Heart Failure With Preserved Ejection Fraction.
    Johannes Burtscher, Martin Burtscher.
      
    DOI:  https://doi.org/10.1001/jamacardio.2023.3574
  60. Eur J Pharmacol. 2023 Oct 06. pii: S0014-2999(23)00597-6. [Epub ahead of print] 176085
    Low-dose atorvastatin protects skeletal muscle mitochondria in high-fat diet-fed mice with mitochondrial autophagy inhibition and fusion enhancement.
    Peng Zheng, Qian Zhang, Wenjing Ma, Ran Hu, Yilu Gu, Zhiping Bian, Di Yang, Xiangjian Chen, Hengfang Wu.
      Despite the great clinical benefits of statins in cardiovascular diseases, their widespread use may lead to adverse muscle reactions associated with mitochondrial dysfunction. Some studies have demonstrated that statins provide substantial improvement to skeletal muscle health in mice. Our previous study found that oral treatment with atorvastatin (Ator, 3 mg/kg) protected myocardial mitochondria in high-fat diet (HFD)-fed mice. Therefore, this study aimed to explore the influence of low-dose Ator (3 mg/kg) on mitochondria in skeletal muscle under cholesterol overload. Male C57BL/6J mice were fed a HFD for 18 weeks and orally administered Ator (3 mg/kg) during the last 12 weeks. Ator treatment had no effects on elevated serum cholesterol and glucose levels in HFD-fed mice. Serum creatine kinase levels and the cross-sectional area of muscle cells were not affected by HFD feeding or Ator treatment. Increased expression of PINK1-LC3 II (activated mitophagy), MFN2 (fusion), and PGC-1α (biogenesis) proteins was induced in the skeletal muscles of HFD-fed mice. Treatment with Ator inhibited PINK1 and LC3 II protein expression, but further promoted MFN1, MFN2, and OPA1 expression. The impairments in mitochondrial quality and morphology in HFD-fed mice was attenuated by treatment with Ator. Furthermore, Ator treatment enhanced glucose oxidation capacity and restored ATP production in the skeletal muscles of HFD-fed mice. The study reveals that low-dose Ator has a protective effect on muscle mitochondria in mice, likely through inhibiting mitophagy and enhancing mitochondrial fusion. This suggests that skeletal muscle mitochondria may be one of low-dose Ator-mediated protective targets.
    Keywords:  Atorvastatin; High cholesterol; High-fat diet; Mitochondria; Mitochondrial quality-control network; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.ejphar.2023.176085
  61. NPJ Biofilms Microbiomes. 2023 Oct 07. 9(1): 74
    Mitochondrial dysfunction promotes microbial composition that negatively impacts on ulcerative colitis development and progression.
    Ainize Peña-Cearra, Deguang Song, Janire Castelo, Ainhoa Palacios, Jose Luis Lavín, Mikel Azkargorta, Felix Elortza, Miguel Fuertes, Miguel Angel Pascual-Itoiz, Diego Barriales, Itziar Martín-Ruiz, Asier Fullaondo, Ana M Aransay, Hector Rodríguez, Noah W Palm, Juan Anguita, Leticia Abecia.
      Recent evidence demonstrates potential links between mitochondrial dysfunction and inflammatory bowel diseases (IBD). In addition, bidirectional interactions between the intestinal microbiota and host mitochondria may modulate intestinal inflammation. We observed previously that mice deficient in the mitochondrial protein MCJ (Methylation-controlled J protein) exhibit increased susceptibility to DSS colitis. However, it is unclear whether this phenotype is primarily driven by MCJ-/- associated gut microbiota dysbiosis or by direct effects of MCJ-deficiency. Here, we demonstrate that fecal microbiota transplantation (FMT) from MCJ-deficient into germ-free mice was sufficient to confer increased susceptibility to colitis. Therefore, an FMT experiment by cohousing was designed to alter MCJ-deficient microbiota. The phenotype resulting from complex I deficiency was reverted by FMT. In addition, we determined the protein expression pathways impacted by MCJ deficiency, providing insight into the pathophysiology of IBD. Further, we used magnetic activated cell sorting (MACS) and 16S rRNA gene sequencing to characterize taxa-specific coating of the intestinal microbiota with Immunoglobulin A (IgA-SEQ) in MCJ-deficient mice. We show that high IgA coating of fecal bacteria observed in MCJ-deficient mice play a potential role in disease progression. This study allowed us to identify potential microbial signatures in feces associated with complex I deficiency and disease progression. This research highlights the importance of finding microbial biomarkers, which might serve as predictors, permitting the stratification of ulcerative colitis (UC) patients into distinct clinical entities of the UC spectrum.
    DOI:  https://doi.org/10.1038/s41522-023-00443-y
  62. Brain. 2023 Oct 13. pii: awad357. [Epub ahead of print]
    Phenotype and natural history of mitochondrial membrane protein-associated neurodegeneration.
    Vassilena Iankova, Peter Sparber, Mohammad Rohani, Petr Dusek, Boriana Büchner, Ivan Karin, Susanne A Schneider, Juan M Gorriz, Tomasz Kmiec, Thomas Klopstock.
      Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an ultraorphan neurogenetic disease from the group of Neurodegeneration with Brain Iron Accumulation (NBIA) disorders. Here we report cross-sectional and longitudinal data to define the phenotype, to assess disease progression, and to estimate sample sizes for clinical trials. We enrolled patients with genetically confirmed MPAN from the Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON) registry and cohort study, and from additional sites. Linear mixed-effect modelling (LMEM) was used to calculate annual progression rates for Unified Parkinson's Disease Rating Scale (UPDRS), Barry-Albright Dystonia (BAD) Scale, Schwab and England Activities of Daily Living (SE-ADL) scale, and the Pediatric Quality of Life Inventory (PedsQL). We investigated 85 MPAN patients cross-sectionally, with functional outcome data collected in 45. Median age at onset was 9 years and the median diagnostic delay was 5 years. The most common findings were gait disturbance (99%), pyramidal involvement (95%), dysarthria (90%), vision disturbances (82%), with all but dysarthria presenting early in the disease course. After 16 years into disease, 50% of patients were wheelchair dependent. LMEM showed an annual progression rate of 4.5 points in total UPDRS. The total BAD scale showed no significant progression over time. The SE-ADL scale, the patient- reported and the parent-reported PedsQL showed a decline of 3.9%, 2.14 and 2.05 points respectively. No patient subpopulations were identified based on longitudinal trajectories. Interpretation: Our cross-sectional results define order of onset and frequency of symptoms in MPAN, which will inform the diagnostic process, help shorten the diagnostic delay, and aid in counselling patients, parents, and caregivers. Our longitudinal findings define the natural history of MPAN, reveal the most responsive outcomes, and highlight the need for an MPAN-specific rating approach. Our sample size estimations inform the design of upcoming clinical trials.
    Keywords:  MPAN; NBIA; mitochondrial membrane protein-associated neurodegeneration; neurodegeneration with brain iron accumulation
    DOI:  https://doi.org/10.1093/brain/awad357
  63. Basic Res Cardiol. 2023 Oct 11. 118(1): 45
    Succinate dehydrogenase is essential for epigenetic and metabolic homeostasis in hearts.
    Wenwen Li, Li Quan, Kun Peng, Yanru Wang, Xianhua Wang, Quan Chen, Heping Cheng, Qi Ma.
      A hallmark of heart failure is a metabolic switch away from fatty acids β-oxidation (FAO) to glycolysis. Here, we show that succinate dehydrogenase (SDH) is required for maintenance of myocardial homeostasis of FAO/glycolysis. Mice with cardiomyocyte-restricted deletion of subunit b or c of SDH developed a dilated cardiomyopathy and heart failure. Hypertrophied hearts displayed a decrease in FAO, while glucose uptake and glycolysis were augmented, which was reversed by enforcing FAO fuels via a high-fat diet, which also improved heart failure of mutant mice. SDH-deficient hearts exhibited an increase in genome-wide DNA methylation associated with accumulation of succinate, a metabolite known to inhibit DNA demethylases, resulting in changes of myocardial transcriptomic landscape. Succinate induced DNA hypermethylation and depressed the expression of FAO genes in myocardium, leading to imbalanced FAO/glycolysis. Inhibition of succinate by α-ketoglutarate restored transcriptional profiles and metabolic disorders in SDH-deficient cardiomyocytes. Thus, our findings reveal the essential role for SDH in metabolic remodeling of failing hearts, and highlight the potential of therapeutic strategies to prevent cardiac dysfunction in the setting of SDH deficiency.
    Keywords:  DNA methylation; Heart failure; Myocardial metabolism; SDH; Succinate
    DOI:  https://doi.org/10.1007/s00395-023-01015-z
  64. bioRxiv. 2023 Sep 29. pii: 2023.09.29.559526. [Epub ahead of print]
    Mitochondrial regulator PGC-1a in neuronal metabolism and brain aging.
    Dylan C Souder, Eric R McGregor, Timothy W Rhoads, Josef P Clark, Tiaira J Porter, Kevin Eliceiri, Darcie L Moore, Luigi Puglielli, Rozalyn M Anderson.
      The brain is a high energy tissue, and the cell types of which it is comprised are distinct in function and in metabolic requirements. The transcriptional co-activator PGC-1a is a master regulator of mitochondrial function and is highly expressed in the brain; however, its cell-type specific role in regulating metabolism has not been well established. Here, we show that PGC-1a is responsive to aging and that expression of the neuron specific PGC-1a isoform allows for specialization in metabolic adaptation. Transcriptional profiles of the cortex from male mice show an impact of age on immune, inflammatory, and neuronal functional pathways and a highly integrated metabolic response that is associated with decreased expression of PGC-1a. Proteomic analysis confirms age-related changes in metabolism and further shows changes in ribosomal and RNA splicing pathways. We show that neurons express a specialized PGC-1a isoform that becomes active during differentiation from stem cells and is further induced during the maturation of isolated neurons. Neuronal but not astrocyte PGC-1a responds robustly to inhibition of the growth sensitive kinase GSK3b, where the brain specific promoter driven dominant isoform is repressed. The GSK3b inhibitor lithium broadly reprograms metabolism and growth signaling, including significantly lower expression of mitochondrial and ribosomal pathway genes and suppression of growth signaling, which are linked to changes in mitochondrial function and neuronal outgrowth. In vivo, lithium treatment significantly changes the expression of genes involved in cortical growth, endocrine, and circadian pathways. These data place the GSK3b/PGC-1a axis centrally in a growth and metabolism network that is directly relevant to brain aging.
    DOI:  https://doi.org/10.1101/2023.09.29.559526
  65. Int J Mol Sci. 2023 Oct 03. pii: 14858. [Epub ahead of print]24(19):
    N6-Methyladenine Progressively Accumulates in Mitochondrial DNA during Aging.
    Ádám Sturm, Himani Sharma, Ferenc Bodnár, Maryam Aslam, Tibor Kovács, Ákos Németh, Bernadette Hotzi, Viktor Billes, Tímea Sigmond, Kitti Tátrai, Balázs Egyed, Blanka Téglás-Huszár, Gitta Schlosser, Nikolaos Charmpilas, Christina Ploumi, András Perczel, Nektarios Tavernarakis, Tibor Vellai.
      N6-methyladenine (6mA) in the DNA is a conserved epigenetic mark with various cellular, physiological and developmental functions. Although the presence of 6mA was discovered a few years ago in the nuclear genome of distantly related animal taxa and just recently in mammalian mitochondrial DNA (mtDNA), accumulating evidence at present seriously questions the presence of N6-adenine methylation in these genetic systems, attributing it to methodological errors. In this paper, we present a reliable, PCR-based method to determine accurately the relative 6mA levels in the mtDNA of Caenorhabditis elegans, Drosophila melanogaster and dogs, and show that these levels gradually increase with age. Furthermore, daf-2(-)-mutant worms, which are defective for insulin/IGF-1 (insulin-like growth factor) signaling and live twice as long as the wild type, display a half rate at which 6mA progressively accumulates in the mtDNA as compared to normal values. Together, these results suggest a fundamental role for mtDNA N6-adenine methylation in aging and reveal an efficient diagnostic technique to determine age using DNA.
    Keywords:  C. elegans; Drosophila; N6-adenine methylation; N6-methyladenine levels; age determination; aging; dog; mitochondrial genome
    DOI:  https://doi.org/10.3390/ijms241914858
  66. Angew Chem Int Ed Engl. 2023 Oct 11. e202312784
    Neuroprotective Bioorthogonal Catalysis in Mitochondria using Protein-Integrated Hydrogen-Bonded Organic Frameworks.
    Jiakang Tang, Ji Liu, Qizhen Zheng, Rui Yao, Ming Wang.
      Mitochondria-targeted bioorthogonal catalysis holds promise for controlling cell function precisely, yet achieving selective and efficient chemical reactions within organelles is challenging. In this study, we introduce a new strategy using protein-integrated hydrogen-bonded organic frameworks (HOFs) to enable synergistic bioorthogonal chemical catalysis and enzymatic catalysis within mitochondria. Utilizing catalytically active tris(4,4'-dicarboxylicacid-2,2'-bipyridyl) ruthenium(II) to self-assemble with [1,1'-biphenyl]-4,4'-biscarboximidamide, we synthesized nanoscale RuB-HOFs that exhibit high photocatalytic reduction activity. Notably, RuB-HOFs efficiently enter cells and preferentially localize to mitochondria, where they facilitate bioorthogonal photoreduction reactions. Moreover, we show that RuB-HOFs encapsulating catalase can produce hydrogen sulfide (H2S) in mitochondria through photocatalytic reduction of pro-H2S and degrade hydrogen peroxide through enzymatic catalysis simultaneously, offering significant neuroprotection effect against oxidative stress. Our findings not only introduce a versatile chemical toolset for mitochondria-targeted bioorthogonal catalysis for prodrug activation but also pave the way for potential therapeutic applications in treating diseases related to cellular oxidative stress.
    Keywords:  Hydrogen-Bonded Organic Frameworks; bioorthogonal catalysis; mitochondrial targeting; neuroprotection; protein delivery
    DOI:  https://doi.org/10.1002/anie.202312784
  67. Lancet Gastroenterol Hepatol. 2023 Oct 05. pii: S2468-1253(23)00241-8. [Epub ahead of print]
    Uncouplers of mitochondrial oxidation in non-alcoholic fatty liver disease.
    Maurice Michel, Jörn M Schattenberg.
      
    DOI:  https://doi.org/10.1016/S2468-1253(23)00241-8
  68. Bioinformation. 2023 ;19(3): 226-229
    Leber hereditary optic neuropathy presenting as bilateral visual loss and white matter disease.
    Hussein Algahtani, Bader Shirah, Angham Abdulrhman Abdulkareem, Fehmida Bibi, Peter Natesan Pushparaj, Muhammad Imran Naseer.
      Leber hereditary optic neuropathy (LHON) is a rare maternally inherited mitochondrial disorder that typically affects young male adults in their second and third decades of life. It usually manifests as painless, subacute, progressive, bilateral vision loss, with more than 90% of affected individuals losing their vision before age 50. Compared with other diseases that cause optic neuritis (multiple sclerosis or neuromyelitis optica spectrum disorders), LHON has worsening visual function in the first 6-12 months of disease progression, is predominantly male, the optic nerve is affected bilaterally from onset, there is no gadolinium enhancement on MRI, no response to disease-modifying therapy, and there is a family history of mutation in mitochondrial DNA. In this article, we describe an interesting and challenging case of LHON due to a homoplasmic variant in the MT -CO3 gene that was initially misdiagnosed as a monophasic demyelinating disorder (clinically isolated syndrome vs acute disseminated encephalomyelitis vs neuromyelitis optica spectrum disorders).
    Keywords:  Acute Disseminated Encephalomyelitis; Leber Hereditary Optic Neuropathy; MT-CO3; Mitochondrial Inheritance; Saudi Arabia
    DOI:  https://doi.org/10.6026/97320630019226
  69. Science. 2023 Oct 13. 382(6667): eadf5357
    Single-cell DNA methylation and 3D genome architecture in the human brain.
    Wei Tian, Jingtian Zhou, Anna Bartlett, Qiurui Zeng, Hanqing Liu, Rosa G Castanon, Mia Kenworthy, Jordan Altshul, Cynthia Valadon, Andrew Aldridge, Joseph R Nery, Huaming Chen, Jiaying Xu, Nicholas D Johnson, Jacinta Lucero, Julia K Osteen, Nora Emerson, Jon Rink, Jasper Lee, Yang E Li, Kimberly Siletti, Michelle Liem, Naomi Claffey, Carolyn O'Connor, Anna Marie Yanny, Julie Nyhus, Nick Dee, Tamara Casper, Nadiya Shapovalova, Daniel Hirschstein, Song-Lin Ding, Rebecca Hodge, Boaz P Levi, C Dirk Keene, Sten Linnarsson, Ed Lein, Bing Ren, M Margarita Behrens, Joseph R Ecker.
      Delineating the gene-regulatory programs underlying complex cell types is fundamental for understanding brain function in health and disease. Here, we comprehensively examined human brain cell epigenomes by probing DNA methylation and chromatin conformation at single-cell resolution in 517 thousand cells (399 thousand neurons and 118 thousand non-neurons) from 46 regions of three adult male brains. We identified 188 cell types and characterized their molecular signatures. Integrative analyses revealed concordant changes in DNA methylation, chromatin accessibility, chromatin organization, and gene expression across cell types, cortical areas, and basal ganglia structures. We further developed single-cell methylation barcodes that reliably predict brain cell types using the methylation status of select genomic sites. This multimodal epigenomic brain cell atlas provides new insights into the complexity of cell-type-specific gene regulation in adult human brains.
    DOI:  https://doi.org/10.1126/science.adf5357
  70. Aging Dis. 2023 Oct 03.
    Mitochondria: A Potential Rejuvenation Tool against Aging.
    Qian Hua Phua, Shi Yan Ng, Boon-Seng Soh.
      Aging is a complex physiological process encompassing both physical and cognitive decline over time. This intricate process is governed by a multitude of hallmarks and pathways, which collectively contribute to the emergence of numerous age-related diseases. In response to the remarkable increase in human life expectancy, there has been a substantial rise in research focusing on the development of anti-aging therapies and pharmacological interventions. Mitochondrial dysfunction, a critical factor in the aging process, significantly impacts overall cellular health. In this extensive review, we will explore the contemporary landscape of anti-aging strategies, placing particular emphasis on the promising potential of mitotherapy as a ground-breaking approach to counteract the aging process. Moreover, we will investigate the successful application of mitochondrial transplantation in both animal models and clinical trials, emphasizing its translational potential. Finally, we will discuss the inherent challenges and future possibilities of mitotherapy within the realm of aging research and intervention.
    DOI:  https://doi.org/10.14336/AD.2023.0712
  71. Nat Commun. 2023 Oct 11. 14(1): 6383
    Glucocerebrosidase mutations disrupt the lysosome and now the mitochondria.
    Andrés D Klein, Tiago Fleming Outeiro.
      
    DOI:  https://doi.org/10.1038/s41467-023-42107-7
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