bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2023–08–13
forty-four papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Mitochondrial encephalomyopathy.
  2. Mitochondrial fission fueled by fasting.
  3. NME6: ribonucleotide salvage sustains mitochondrial transcription.
  4. ATAD3A: A Key Regulator of Mitochondria-Associated Diseases.
  5. Leigh syndrome: an adult presentation of a paediatric disease.
  6. Structure and dynamics of the mitochondrial DNA-compaction factor Abf2 from S. cerevisiae.
  7. The complexities of investigating mitochondria dynamics in multiple sclerosis and mouse models of MS.
  8. Parkinson's disease neurons exhibit alterations in mitochondrial quality control proteins.
  9. Integrative omics approaches to advance rare disease diagnostics.
  10. Specifications of the ACMG/AMP guidelines for ACADVL variant interpretation.
  11. Brain mitochondrial diversity and network organization predict anxiety-like behavior in male mice.
  12. A Novel Interaction between MFN2/Marf and MARK4/PAR-1 is Implicated in Synaptic Defects and Mitochondrial Dysfunction.
  13. Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene.
  14. FBXL4 mutations cause excessive mitophagy via BNIP3/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome.
  15. Structural basis for a degenerate tRNA identity code and the evolution of bimodal specificity in human mitochondrial tRNA recognition.
  16. RetroGREAT signaling: The lessons we learn from yeast.
  17. Under-fuelling the fire: mitochondrial implications for energy deficiency and muscle protein synthesis.
  18. Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54.
  19. Mitochondria-mediated Ferroptosis in Diseases Therapy: From Molecular Mechanisms to Implications.
  20. Current and Future Landscape in Genetic Therapies for Leber Hereditary Optic Neuropathy.
  21. Full-length Isoform Sequencing for Resolving the Molecular Basis of Charcot-Marie-Tooth 2A.
  22. Peripheral macrophages drive CNS disease in the Ndufs4(-/-) model of Leigh syndrome.
  23. Exploring Molecular Targets for Mitochondrial Therapies in Neurodegenerative Diseases.
  24. FGF21 and GDF15 are elevated in Barth Syndrome and are correlated to important clinical measures.
  25. Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor.
  26. Molecular insights into the catalysis and regulation of mammalian NAD-dependent isocitrate dehydrogenases.
  27. Mitochondrial integrated stress response controls lung epithelial cell fate.
  28. Molecular basis of Mg2+ permeation through the human mitochondrial Mrs2 channel.
  29. DELE1 oligomerization promotes integrated stress response activation.
  30. Use of genome sequencing to hunt for cryptic second-hit variants: analysis of 31 cases recruited to the 100 000 Genomes Project.
  31. Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling.
  32. Cross-protein transfer learning substantially improves disease variant prediction.
  33. Malonyl-CoA links lipid metabolism to nutrient signalling by directly inhibiting mTORC1.
  34. The Reduction in the Mitochondrial Membrane Potential in Aging: The Role of the Mitochondrial Permeability Transition Pore.
  35. Polymorphic variants at NDUFC2, encoding a mitochondrial complex I subunit, associate with cardiac hypertrophy in human hypertension.
  36. Genome-wide prediction of disease variant effects with a deep protein language model.
  37. White adipose tissue mitochondrial bioenergetics in metabolic diseases.
  38. Mitochondrial Dysfunction Associated with mtDNA in Metabolic Syndrome and Obesity.
  39. A novel ELOVL4 variant, L168S, causes early childhood-onset Spinocerebellar ataxia-34 and retinal dysfunction: a case report.
  40. The application of long-read sequencing in clinical settings.
  41. Exome and genome sequencing for rare genetic disease diagnosis: A scoping review and critical appraisal of clinical guidance documents produced by genetics professional organizations.
  42. Universal DNA methylation age across mammalian tissues.
  43. Genetic etiology of progressive pediatric neurological disorders.
  44. Case report: Asp194Ala variant in MFN2 is associated with ALS-FTD in an Italian family.
  1. Handb Clin Neurol. 2023 ;pii: B978-0-323-98818-6.00025-X. [Epub ahead of print]195 563-585
    Mitochondrial encephalomyopathy.
    Yi Shiau Ng, Robert McFarland.
      Mitochondrial dysfunction, especially perturbation of oxidative phosphorylation and adenosine triphosphate (ATP) generation, disrupts cellular homeostasis and is a surprisingly frequent cause of central and peripheral nervous system pathology. Mitochondrial disease is an umbrella term that encompasses a host of clinical syndromes and features caused by in excess of 300 different genetic defects affecting the mitochondrial and nuclear genomes. Patients with mitochondrial disease can present at any age, ranging from neonatal onset to late adult life, with variable organ involvement and neurological manifestations including neurodevelopmental delay, seizures, stroke-like episodes, movement disorders, optic neuropathy, myopathy, and neuropathy. Until relatively recently, analysis of skeletal muscle biopsy was the focus of diagnostic algorithms, but step-changes in the scope and availability of next-generation sequencing technology and multiomics analysis have revolutionized mitochondrial disease diagnosis. Currently, there is no specific therapy for most types of mitochondrial disease, although clinical trials research in the field is gathering momentum. In that context, active management of epilepsy, stroke-like episodes, dystonia, brainstem dysfunction, and Parkinsonism are all the more important in improving patient quality of life and reducing mortality.
    Keywords:  Ataxia; CPEO; Leigh syndrome; MELAS; Mitochondrial DNA; Movement disorders; Myopathy; Neuropathy
    DOI:  https://doi.org/10.1016/B978-0-323-98818-6.00025-X
  2. Sci Signal. 2023 08 08. 16(797): eadk1008
    Mitochondrial fission fueled by fasting.
    Wei Wong.
      Fasting activates mTORC2 to stimulate mitochondrial fission and support mitochondrial respiration.
    DOI:  https://doi.org/10.1126/scisignal.adk1008
  3. EMBO J. 2023 Aug 07. e114990
    NME6: ribonucleotide salvage sustains mitochondrial transcription.
    Paulina H Wanrooij, Andrei Chabes.
      The building blocks for RNA and DNA are made in the cytosol, meaning mitochondria depend on the import and salvage of ribonucleoside triphosphates (rNTPs) and deoxyribonucleoside triphosphates (dNTPs) for the synthesis of their own genetic material. While extensive research has focused on mitochondrial dNTP homeostasis due to its defects being associated with various mitochondrial DNA (mtDNA) depletion and deletion syndromes, the investigation of mitochondrial rNTP homeostasis has received relatively little attention. In this issue of the EMBO Journal, Grotehans et al provide compelling evidence of a major role for NME6, a mitochondrial nucleoside diphosphate kinase, in the conversion of pyrimidine ribonucleoside diphosphates into the corresponding triphosphates. These data also suggest a significant physiological role for NME6, as its absence results in the depletion of mitochondrial transcripts and destabilization of the electron transport chain (Grotehans et al, 2023).
    DOI:  https://doi.org/10.15252/embj.2023114990
  4. Int J Mol Sci. 2023 Aug 07. pii: 12511. [Epub ahead of print]24(15):
    ATAD3A: A Key Regulator of Mitochondria-Associated Diseases.
    Liting Chen, Yuchang Li, Alexander Zambidis, Vassilios Papadopoulos.
      Mitochondrial membrane protein ATAD3A is a member of the AAA-domain-containing ATPases superfamily. It is important for the maintenance of mitochondrial DNA, structure, and function. In recent years, an increasing number of ATAD3A mutations have been identified in patients with neurological symptoms. Many of these mutations disrupt mitochondrial structure, function, and dynamics and are lethal to patients at a young age. Here, we summarize the current understanding of the relationship between ATAD3A and mitochondria, including the interaction of ATAD3A with mitochondrial DNA and mitochondrial/ER proteins, the regulation of ATAD3A in cholesterol mitochondrial trafficking, and the effect of known ATAD3A mutations on mitochondrial function. In the current review, we revealed that the oligomerization and interaction of ATAD3A with other mitochondrial/ER proteins are vital for its various functions. Despite affecting different domains of the protein, nearly all documented mutations observed in ATAD3A exhibit either loss-of-function or dominant-negative effects, potentially leading to disruption in the dimerization of ATAD3A; autophagy; mitophagy; alteration in mitochondrial number, size, and cristae morphology; and diminished activity of mitochondrial respiratory chain complexes I, IV, and V. These findings imply that ATAD3A plays a critical role in mitochondrial dynamics, which can be readily perturbed by ATAD3A mutation variants.
    Keywords:  ATAD3A; cancer; cholesterol; mitochondria; mitochondrial respiration; mtDNA; mutation; neurological diseases
    DOI:  https://doi.org/10.3390/ijms241512511
  5. Pract Neurol. 2023 Aug 11. pii: pn-2023-003862. [Epub ahead of print]
    Leigh syndrome: an adult presentation of a paediatric disease.
    Taylor Watson-Fargie, Victoria Marshall, Natasha E Fullerton, Veronica Leach, Daniela Pilz, Charlotte V Y Hemingbrough, Sila Hopton, Robert W Taylor, Yi S Ng, Andrew Schaefer, Gráinne S Gorman, Maria Elena Farrugia.
      A previously healthy 27-year-old man was admitted to the acute neurology ward with events involving his face, throat and upper limb, which video telemetry later confirmed were refractory focal seizures. He also had progressive pyramidal features, dysarthria and ataxia. MR scans of the brain identified progressive bilateral basal ganglia abnormalities, consistent with Leigh syndrome. However, extensive laboratory and genetic panels did not give a unifying diagnosis. A skeletal muscle biopsy showed no histopathological abnormalities on routine stains. Sequencing of the entire mitochondrial genome in skeletal muscle identified a well-characterised pathogenic variant (m.10191T>C in MT-ND3; NC_012920.1) at 85% heteroplasmy in skeletal muscle. We discuss the clinical and molecular diagnosis of an adult presenting with Leigh syndrome, which is more commonly a paediatric presentation of mitochondrial disease, and how early recognition of a mitochondrial cause is important to support patient care.
    Keywords:  CLINICAL NEUROLOGY; METABOLIC DISEASE; MITOCHONDRIAL DISORDERS; NEUROGENETICS
    DOI:  https://doi.org/10.1136/pn-2023-003862
  6. J Struct Biol. 2023 Aug 03. pii: S1047-8477(23)00071-0. [Epub ahead of print] 108008
    Structure and dynamics of the mitochondrial DNA-compaction factor Abf2 from S. cerevisiae.
    Jens Lidman, Ylber Sallova, Irena Matečko-Burmann, Björn M Burmann.
      Mitochondria are essential organelles that produce most of the energy via the oxidative phosphorylation (OXPHOS) system in all eukaryotic cells. Several essential subunits of the OXPHOS system are encoded by the mitochondrial genome (mtDNA) despite its small size. Defects in mtDNA maintenance and expression can lead to severe OXPHOS deficiencies and are amongst the most common causes of mitochondrial disease. The mtDNA is packaged as nucleoprotein structures, referred to as nucleoids. The conserved mitochondrial proteins, ARS-binding factor 2 (Abf2) in the budding yeast Saccharomyces cerevisiae (S. cerevisiae) and mitochondrial transcription factor A (TFAM) in mammals, are nucleoid associated proteins (NAPs) acting as condensing factors needed for packaging and maintenance of the mtDNA. Interestingly, gene knockout of Abf2 leads, in yeast, to the loss of mtDNA and respiratory growth, providing evidence for its crucial role. On a structural level, the condensing factors usually contain two DNA binding domains called high-mobility group boxes (HMG boxes). The co-operating mechanical activities of these domains are crucial in establishing the nucleoid architecture by bending the DNA strands. Here we used advanced solution NMR spectroscopy methods to characterize the dynamical properties of Abf2 together with its interaction with DNA. We find that the two HMG-domains react notably different to external cues like temperature and salt, indicating distinct functional properties. Biophysical characterizations show the pronounced difference of these domains upon DNA-binding, suggesting a refined picture of the Abf2 functional cycle.
    Keywords:  ABF2; HMG-boxes; mitochondrial DNA packaging; protein dynamics
    DOI:  https://doi.org/10.1016/j.jsb.2023.108008
  7. Front Neurosci. 2023 ;17 1144896
    The complexities of investigating mitochondria dynamics in multiple sclerosis and mouse models of MS.
    Kelley C Atkinson, Marvellous Osunde, Seema K Tiwari-Woodruff.
      Multiple sclerosis (MS) is a demyelinating, degenerating disorder of the central nervous system (CNS) that is accompanied by mitochondria energy production failure. A loss of myelin paired with a deficit in energy production can contribute to further neurodegeneration and disability in patients in MS. Mitochondria are essential organelles that produce adenosine triphosphate (ATP) via oxidative phosphorylation in all cells in the CNS, including neurons, oligodendrocytes, astrocytes, and immune cells. In the context of demyelinating diseases, mitochondria have been shown to alter their morphology and undergo an initial increase in metabolic demand. This is followed by mitochondrial respiratory chain deficiency and abnormalities in mitochondrial transport that contribute to progressive neurodegeneration and irreversible disability. The current methodologies to study mitochondria are limiting and are capable of providing only a partial snapshot of the true mitochondria activity at a particular timepoint during disease. Mitochondrial functional studies are mostly performed in cell culture or whole brain tissue, which prevents understanding of mitochondrial pathology in distinct cell types in vivo. A true understanding of cell-specific mitochondrial pathophysiology of MS in mouse models is required. Cell-specific mitochondria morphology, mitochondria motility, and ATP production studies in animal models of MS will help us understand the role of mitochondria in the normal and diseased CNS. In this review, we present currently used methods to investigate mitochondria function in MS mouse models and discuss the current advantages and caveats with using each technique. In addition, we present recently developed mitochondria transgenic mouse lines expressing Cre under the control of CNS specific promoters to relate mitochondria to disease in vivo.
    Keywords:  EAE; cuprizone; demyelination; inflammation; mitochondria; multiple sclerosis; myelin; remyelination
    DOI:  https://doi.org/10.3389/fnins.2023.1144896
  8. NPJ Parkinsons Dis. 2023 Aug 08. 9(1): 120
    Parkinson's disease neurons exhibit alterations in mitochondrial quality control proteins.
    Chun Chen, David McDonald, Alasdair Blain, Emily Mossman, Kiera Atkin, Michael F Marusich, Roderick Capaldi, Laura Bone, Anna Smith, Andrew Filby, Daniel Erskine, Oliver Russell, Gavin Hudson, Amy E Vincent, Amy K Reeve.
      Mitochondrial dysfunction has been suggested to contribute to Parkinson's disease pathogenesis, though an understanding of the extent or exact mechanism of this contribution remains elusive. This has been complicated by challenging nature of pathway-based analysis and an inability simultaneously study multiple related proteins within human brain tissue. We used imaging mass cytometry (IMC) to overcome these challenges, measuring multiple protein targets, whilst retaining the spatial relationship between targets in post-mortem midbrain sections. We used IMC to simultaneously interrogate subunits of the mitochondrial oxidative phosphorylation complexes, and several key signalling pathways important for mitochondrial homoeostasis, in a large cohort of PD patient and control cases. We revealed a generalised and synergistic reduction in mitochondrial quality control proteins in dopaminergic neurons from Parkinson's patients. Further, protein-protein abundance relationships appeared significantly different between PD and disease control tissue. Our data showed a significant reduction in the abundance of PINK1, Parkin and phosphorylated ubiquitinSer65, integral to the mitophagy machinery; two mitochondrial chaperones, HSP60 and PHB1; and regulators of mitochondrial protein synthesis and the unfolded protein response, SIRT3 and TFAM. Further, SIRT3 and PINK1 did not show an adaptive response to an ATP synthase defect in the Parkinson's neurons. We also observed intraneuronal aggregates of phosphorylated ubiquitinSer65, alongside increased abundance of mitochondrial proteases, LONP1 and HTRA2, within the Parkinson's neurons with Lewy body pathology, compared to those without. Taken together, these findings suggest an inability to turnover mitochondria and maintain mitochondrial proteostasis in Parkinson's neurons. This may exacerbate the impact of oxidative phosphorylation defects and ageing related oxidative stress, leading to neuronal degeneration. Our data also suggest that that Lewy pathology may affect mitochondrial quality control regulation through the disturbance of mitophagy and intramitochondrial proteostasis.
    DOI:  https://doi.org/10.1038/s41531-023-00564-3
  9. J Inherit Metab Dis. 2023 Aug 08.
    Integrative omics approaches to advance rare disease diagnostics.
    Dmitrii Smirnov, Nikita Konstantinovskiy, Holger Prokisch.
      Over the past decade high-throughput DNA sequencing approaches, namely whole exome and whole genome sequencing became a standard procedure in Mendelian disease diagnostics. Implementation of these technologies greatly facilitated diagnostics and shifted the analysis paradigm from variant identification to prioritisation and evaluation. The diagnostic rates vary widely depending on the cohort size, heterogeneity, and disease and range from around 30% to 50% leaving the majority of patients undiagnosed. Advances in omics technologies and computational analysis provide an opportunity to increase these unfavourable rates by providing evidence for disease-causing variant validation and prioritisation. This review aims to provide an overview of the current application of several omics technologies including RNA-sequencing, proteomics, metabolomics and DNA-methylation profiling for diagnostics of rare genetic diseases in general and inborn errors of metabolism in particular. This article is protected by copyright. All rights reserved.
    Keywords:  RNA sequencing; episignatures; methylomics; multi-omics; proteomics; rare genetic disorders
    DOI:  https://doi.org/10.1002/jimd.12663
  10. Mol Genet Metab. 2023 Jul 26. pii: S1096-7192(23)00298-6. [Epub ahead of print]140(3): 107668
    Specifications of the ACMG/AMP guidelines for ACADVL variant interpretation.
    May Flowers, Alexa Dickson, Marcus J Miller, Elaine Spector, Gregory Mark Enns, Heather Baudet, Marzia Pasquali, Lemuel Racacho, Kianoush Sadre-Bazzaz, Ting Wen, Melissa Fogarty, Raquel Fernandez, Meredith A Weaver, Annette Feigenbaum, Brett H Graham, Rong Mao.
      Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is a relatively common inborn error of metabolism, but due to difficulty in accurately predicting affected status through newborn screening, molecular confirmation of the causative variants by sequencing of the ACADVL gene is necessary. Although the ACMG/AMP guidelines have helped standardize variant classification, ACADVL variant classification remains disparate due to a phenotype that can be nonspecific, the possibility of variants that produce late-onset disease, and relatively high carrier frequency, amongst other challenges. Therefore, an ACADVL-specific variant curation expert panel (VCEP) was created to facilitate the specification of the ACMG/AMP guidelines for VLCADD. We expect these guidelines to help streamline, increase concordance, and expedite the classification of ACADVL variants.
    Keywords:  ACADVL; ClinGen; Pathogenicity; Variant interpretation
    DOI:  https://doi.org/10.1016/j.ymgme.2023.107668
  11. Nat Commun. 2023 Aug 10. 14(1): 4726
    Brain mitochondrial diversity and network organization predict anxiety-like behavior in male mice.
    Ayelet M Rosenberg, Manish Saggar, Anna S Monzel, Jack Devine, Peter Rogu, Aaron Limoges, Alex Junker, Carmen Sandi, Eugene V Mosharov, Dani Dumitriu, Christoph Anacker, Martin Picard.
      The brain and behavior are under energetic constraints, limited by mitochondrial energy transformation capacity. However, the mitochondria-behavior relationship has not been systematically studied at a brain-wide scale. Here we examined the association between multiple features of mitochondrial respiratory chain capacity and stress-related behaviors in male mice with diverse behavioral phenotypes. Miniaturized assays of mitochondrial respiratory chain enzyme activities and mitochondrial DNA (mtDNA) content were deployed on 571 samples across 17 brain areas, defining specific patterns of mito-behavior associations. By applying multi-slice network analysis to our brain-wide mitochondrial dataset, we identified three large-scale networks of brain areas with shared mitochondrial signatures. A major network composed of cortico-striatal areas exhibited the strongest mitochondria-behavior correlations, accounting for up to 50% of animal-to-animal behavioral differences, suggesting that this mito-based network is functionally significant. The mito-based brain networks also overlapped with regional gene expression and structural connectivity, and exhibited distinct molecular mitochondrial phenotype signatures. This work provides convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct, behaviorally-relevant mitochondrial phenotypes exist across the male mouse brain.
    DOI:  https://doi.org/10.1038/s41467-023-39941-0
  12. eNeuro. 2023 Aug 04. pii: ENEURO.0409-22.2023. [Epub ahead of print]
    A Novel Interaction between MFN2/Marf and MARK4/PAR-1 is Implicated in Synaptic Defects and Mitochondrial Dysfunction.
    Yeongmi Cheon, Sunggyu Yoon, Jae-Hyuk Lee, Kiyoung Kim, Hyung-Jun Kim, Sung Wook Hong, Ye-Rang Yun, Jiwon Shim, Sung-Hak Kim, Bingwei Lu, Mihye Lee, Seongsoo Lee.
      As cellular energy powerhouses, mitochondria undergo constant fission and fusion to maintain functional homeostasis. The conserved dynamin-like GTPase, MFN2/Marf, plays a role in mitochondrial fusion, mutations of which are implicated in age-related human diseases, including several neurodegenerative disorders. However, the regulation of MFN2/Marf-mediated mitochondrial fusion, as well as the pathologic mechanism of neurodegeneration, are not clearly understood. Here, we identified a novel interaction between MFN2/Marf and MARK4/PAR-1. In the Drosophila larval neuromuscular junction, muscle-specific overexpression of MFN2/Marf decreased the number of synaptic boutons, and the loss of MARK4/PAR-1 alleviated the synaptic defects of MFN2/Marf overexpression. Downregulation of MARK4/PAR-1 rescued the mitochondrial hyperfusion phenotype caused by MFN2/Marf overexpression in the Drosophila muscles as well as in the cultured cells. In addition, knockdown of MARK4/PAR-1 rescued the respiratory dysfunction of mitochondria induced by MFN2/Marf overexpression in mammalian cells. Taken together, our results indicate that the interaction between MFN2/Marf and MARK4/PAR-1 is fine-tuned to maintain synaptic integrity and mitochondrial homeostasis, and its dysregulation may be implicated in neurologic pathogenesis.Significance StatementWe identified a novel interaction between MFN2/Marf and a kinase MARK4/PAR-1 in Drosophila and mammalian cells. The MFN2/Marf and MARK4/PAR-1 interaction was critical for maintaining the synaptic structure of neuromuscular junctions in Drosophila In addition, we found that concomitant knockdown of MARK4/PAR-1 could rescue the mitochondrial hyperfusion and aberrant respiratory function caused by MFN2/Marf overexpression. Our study provides new insights into the link between mitochondrial defects and neurodegeneration, which makes a significant contribution to the understanding of neurologic pathogenesis and therapeutic development.
    Keywords:  Drosophila melanogaster; MARK4/PAR-1; MFN2/Marf; Mitochondrial dynamics; Neurodegenerative disease
    DOI:  https://doi.org/10.1523/ENEURO.0409-22.2023
  13. Am J Med Genet A. 2023 Aug 11.
    Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene.
    Nikolaos Gkiourtzis, Despoina Tramma, Kyriaki Papadopoulou-Legbelou, Maria Moutafi, Athanasios Evangeliou.
      Mitochondrial myopathy is a severe metabolic myopathy related to nuclear or mitochondrial DNA dysfunction. We present a rare case of mitochondrial myopathy, presented with multiple episodes of proximal muscle weakness, lactic acidosis, and severe rhabdomyolysis (CPK 319,990 U/L, lactic acid 22.31 mmol/L, and GFR 3.82 mL/min/1.73m2 ). She was hospitalized in the pediatric intensive care unit due to acute kidney injury, elevated blood pressure, and deterioration of respiratory and cardiac function. Investigation for inherited metabolic disorders showed elevated levels of ammonia, lactic acid to pyruvic acid ratio, and urine ketone bodies. Exome sequencing detected a homozygous pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T) and a heterozygous variant of uncertain significance in MSTO1 (ENST00000538143:p.Leu137Pro/c.410 T > C). After Sanger sequencing, the p.Met4Leu pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T) was identified in a heterozygous state in both her parents and sister. Recently, pathogenic variants in the FDX2 gene have been associated with mitochondrial myopathy, lactic acidosis, optic atrophy, and leukoencephalopathy. Only four reports of FDX2-related rhabdomyolysis have been described before, but none of the previous patients had hyperammonemia. This is a rare case of severe mitochondrial myopathy in a pediatric patient related to a pathogenic FDX2 variant, suggesting the need for genetic analysis of the FDX2 gene in cases of suspicion of mitochondrial myopathies.
    Keywords:  FDX2; children; ferredoxin; lactic acidosis; mitochondrial myopathy; rhabdomyolysis
    DOI:  https://doi.org/10.1002/ajmg.a.63368
  14. Cell Death Differ. 2023 Aug 11.
    FBXL4 mutations cause excessive mitophagy via BNIP3/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome.
    Yingji Chen, Dongyue Jiao, Yang Liu, Xiayun Xu, Yilin Wang, Xiaona Luo, Hexige Saiyin, Yao Li, Kun Gao, Yucai Chen, Shi-Min Zhao, Lixiang Ma, Chenji Wang.
      Mitochondria are essential organelles found in eukaryotic cells that play a crucial role in ATP production through oxidative phosphorylation (OXPHOS). Mitochondrial DNA depletion syndrome (MTDPS) is a group of genetic disorders characterized by the reduction of mtDNA copy number, leading to deficiencies in OXPHOS and mitochondrial functions. Mutations in FBXL4, a substrate-binding adaptor of Cullin 1-RING ubiquitin ligase complex (CRL1), are associated with MTDPS, type 13 (MTDPS13). Here, we demonstrate that, FBXL4 directly interacts with the mitophagy cargo receptors BNIP3 and BNIP3L, promoting their degradation through the ubiquitin-proteasome pathway via the assembly of an active CRL1FBXL4 complex. However, MTDPS13-associated FBXL4 mutations impair the assembly of an active CRL1FBXL4 complex. This results in a notable accumulation of BNIP3/3L proteins and robust mitophagy even at basal levels. Excessive mitophagy was observed in Knockin (KI) mice carrying a patient-derived FBXL4 mutation and cortical neurons (CNs)-induced from MTDPS13 patient human induced pluripotent stem cells (hiPSCs). In summary, our findings suggest that abnormal activation of BNIP3/BNIP3L-dependent mitophagy impairs mitochondrial homeostasis and underlies FBXL4-mutated MTDPS13.
    DOI:  https://doi.org/10.1038/s41418-023-01205-1
  15. Nat Commun. 2023 08 09. 14(1): 4794
    Structural basis for a degenerate tRNA identity code and the evolution of bimodal specificity in human mitochondrial tRNA recognition.
    Bernhard Kuhle, Marscha Hirschi, Lili K Doerfel, Gabriel C Lander, Paul Schimmel.
      Animal mitochondrial gene expression relies on specific interactions between nuclear-encoded aminoacyl-tRNA synthetases and mitochondria-encoded tRNAs. Their evolution involves an antagonistic interplay between strong mutation pressure on mtRNAs and selection pressure to maintain their essential function. To understand the molecular consequences of this interplay, we analyze the human mitochondrial serylation system, in which one synthetase charges two highly divergent mtRNASer isoacceptors. We present the cryo-EM structure of human mSerRS in complex with mtRNASer(UGA), and perform a structural and functional comparison with the mSerRS-mtRNASer(GCU) complex. We find that despite their common function, mtRNASer(UGA) and mtRNASer(GCU) show no constrain to converge on shared structural or sequence identity motifs for recognition by mSerRS. Instead, mSerRS evolved a bimodal readout mechanism, whereby a single protein surface recognizes degenerate identity features specific to each mtRNASer. Our results show how the mutational erosion of mtRNAs drove a remarkable innovation of intermolecular specificity rules, with multiple evolutionary pathways leading to functionally equivalent outcomes.
    DOI:  https://doi.org/10.1038/s41467-023-40354-2
  16. IUBMB Life. 2023 Aug 10.
    RetroGREAT signaling: The lessons we learn from yeast.
    Thi Hoang Diu Bui, Karolina Labedzka-Dmoch.
      The mitochondrial retrograde signaling (RTG) pathway of communication from mitochondria to the nucleus was first studied in yeast Saccharomyces cerevisiae. It rewires cellular metabolism according to the mitochondrial state by reprogramming nuclear gene expression in response to mitochondrial triggers. The main players involved in retrograde signaling are the Rtg1 and Rtg3 transcription factors, and a set of positive and negative regulators, including the Rtg2, Mks1, Lst8, and Bmh1/2 proteins. Retrograde regulation is integrated with other processes, including stress response, osmoregulation, and nutrient sensing through functional crosstalk with cellular pathways such as high osmolarity glycerol or target of rapamycin signaling. In this review, we summarize metabolic changes observed upon retrograde stimulation and analyze the progress made to uncover the mechanisms underlying the integration of regulatory circuits. Comparisons of the evolutionary adaptations of the retrograde pathway that have occurred in the different yeast groups can help to fully understand the process.
    Keywords:  RTG signaling; mitochondria; retrograde response; yeast
    DOI:  https://doi.org/10.1002/iub.2775
  17. J Physiol. 2023 Aug 09.
    Under-fuelling the fire: mitochondrial implications for energy deficiency and muscle protein synthesis.
    Rachel M Handy, Geneviève J DesOrmeaux.
      
    Keywords:  low energy availability; mitochondrial function; muscle protein synthesis
    DOI:  https://doi.org/10.1113/JP285175
  18. Eur J Hum Genet. 2023 Aug 09.
    Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54.
    Thomas B Smith, Alessandro Rea, Huw B Thomas, Kyle Thompson, Monika Oláhová, Reza Maroofian, Mina Zamani, Langping He, Saeid Sadeghian, Hamid Galehdari, Nava Shaul Lotan, Tal Gilboa, Kristin C Herman, Thomas J McCorvie, Wyatt W Yue, Henry Houlden, Robert W Taylor, William G Newman, Raymond T O'Keefe.
      Biallelic hypomorphic variants in PRORP have been recently described as causing the autosomal recessive disorder combined oxidative phosphorylation deficiency type 54 (COXPD54). COXPD54 encompasses a phenotypic spectrum of sensorineural hearing loss and ovarian insufficiency (Perrault syndrome) to leukodystrophy. Here, we report three additional families with homozygous missense PRORP variants with pleiotropic phenotypes. Each missense variant altered a highly conserved residue within the metallonuclease domain. In vitro mitochondrial tRNA processing assays with recombinant TRMT10C, SDR5C1 and PRORP indicated two COXPD54-associated PRORP variants, c.1159A>G (p.Thr387Ala) and c.1241C>T (p.Ala414Val), decreased pre-tRNAIle cleavage, consistent with both variants impacting tRNA processing. No significant decrease in tRNA processing was observed with PRORP c.1093T>C (p.Tyr365His), which was identified in an individual with leukodystrophy. These data provide independent evidence that PRORP variants are associated with COXPD54 and that the assessment of 5' leader mitochondrial tRNA processing is a valuable assay for the functional analysis and clinical interpretation of novel PRORP variants.
    DOI:  https://doi.org/10.1038/s41431-023-01437-2
  19. Aging Dis. 2023 Jul 28.
    Mitochondria-mediated Ferroptosis in Diseases Therapy: From Molecular Mechanisms to Implications.
    Fuhai Feng, Shasha He, Xiaoling Li, Jiake He, Lianxiang Luo.
      Ferroptosis, a type of cell death involving iron and lipid peroxidation, has been found to be closely associated with the development of many diseases. Mitochondria are vital components of eukaryotic cells, serving important functions in energy production, cellular metabolism, and apoptosis regulation. Presently, the precise relationship between mitochondria and ferroptosis remains unclear. In this study, we aim to systematically elucidate the mechanisms via which mitochondria regulate ferroptosis from multiple perspectives to provide novel insights into mitochondrial functions in ferroptosis. Additionally, we present a comprehensive overview of how mitochondria contribute to ferroptosis in different conditions, including cancer, cardiovascular disease, inflammatory disease, mitochondrial DNA depletion syndrome, and novel coronavirus pneumonia. Gaining a comprehensive understanding of the involvement of mitochondria in ferroptosis could lead to more effective approaches for both basic cell biology studies and medical treatments.
    DOI:  https://doi.org/10.14336/AD.2023.0717
  20. Cells. 2023 Aug 07. pii: 2013. [Epub ahead of print]12(15):
    Current and Future Landscape in Genetic Therapies for Leber Hereditary Optic Neuropathy.
    Hoda Shamsnajafabadi, Robert E MacLaren, Jasmina Cehajic-Kapetanovic.
      Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial genetic disease that causes blindness in young adults. Over 50 inherited mitochondrial DNA (mtDNA) variations are associated with LHON; however, more than 95% of cases are caused by one of three missense variations (m.11778 G > A, m.3460 G > A, and m.14484 T > C) encoding for subunits ND4, ND1, and ND6 of the respiration complex I, respectively. These variants remain silent until further and currently poorly understood genetic and environmental factors precipitate the visual loss. The clinical course that ensues is variable, and a convincing treatment for LHON has yet to emerge. In 2015, an antioxidant idebenone (Raxone) received European marketing authorisation to treat visual impairment in patients with LHON, and since then it was introduced into clinical practice in several European countries. Alternative therapeutic strategies, including gene therapy and gene editing, antioxidant and neurotrophic agents, mitochondrial biogenesis, mitochondrial replacement, and stem cell therapies are being investigated in how effective they might be in altering the course of the disease. Allotopic gene therapies are in the most advanced stage of development (phase III clinical trials) whilst most other agents are in phase I or II trials or at pre-clinical stages. This manuscript discusses the phenotype and genotype of the LHON disease with complexities and peculiarities such as incomplete penetrance and gender bias, which have challenged the therapies in development emphasising the most recent use of gene therapy. Furthermore, we review the latest results of the three clinical trials based on adeno-associated viral (AAV) vector-mediated delivery of NADH dehydrogenase subunit 4 (ND4) with mitochondrial targeting sequence, highlighting the differences in the vector design and the rationale behind their use in the allotopic transfer.
    Keywords:  LHON; NADH dehydrogenase; gene therapy; idebenone; leber hereditary optic neuropathy; mitochondrial inheritance; retinal ganglion cells
    DOI:  https://doi.org/10.3390/cells12152013
  21. Neurol Genet. 2023 Oct;9(5): e200090
    Full-length Isoform Sequencing for Resolving the Molecular Basis of Charcot-Marie-Tooth 2A.
    for University of Washington Center for Mendelian Genomics (UW-CMG), and Undiagnosed Diseases Network (UDN),
       Objectives: Transcript sequencing of patient-derived samples has been shown to improve the diagnostic yield for solving cases of suspected Mendelian conditions, yet the added benefit of full-length long-read transcript sequencing is largely unexplored.
    Methods: We applied short-read and full-length transcript sequencing and mitochondrial functional studies to a patient-derived fibroblast cell line from an individual with neuropathy that previously lacked a molecular diagnosis.
    Results: We identified an intronic homozygous MFN2 c.600-31T>G variant that disrupts the branch point critical for intron 6 splicing. Full-length long-read isoform complementary DNA (cDNA) sequencing after treatment with a nonsense-mediated mRNA decay (NMD) inhibitor revealed that this variant creates 5 distinct altered splicing transcripts. All 5 altered splicing transcripts have disrupted open reading frames and are subject to NMD. Furthermore, a patient-derived fibroblast line demonstrated abnormal lipid droplet formation, consistent with MFN2 dysfunction. Although correctly spliced full-length MFN2 transcripts are still produced, this branch point variant results in deficient MFN2 levels and autosomal recessive Charcot-Marie-Tooth disease, axonal, type 2A (CMT2A).
    Discussion: This case highlights the utility of full-length isoform sequencing for characterizing the molecular mechanism of undiagnosed rare diseases and expands our understanding of the genetic basis for CMT2A.
    DOI:  https://doi.org/10.1212/NXG.0000000000200090
  22. Brain Pathol. 2023 Aug 08. e13192
    Peripheral macrophages drive CNS disease in the Ndufs4(-/-) model of Leigh syndrome.
    Allison R Hanaford, Asheema Khanna, Vivian Truong, Katerina James, Yihan Chen, Michael Mulholland, Bernhard Kayser, Ryan W Liao, Margaret Sedensky, Phil Morgan, Nathan Baerchst, Vandana Kalia, Surojit Sarkar, Simon C Johnson.
      Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi-system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, and necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high-dose pexidartinib, a CSF1R inhibitor, prevents LS CNS lesions and systemic disease in the Ndufs4(-/-) mouse model of LS. While the dose-response in this study implicated peripheral immune cells, the immune populations involved have not yet been elucidated. Here, we used a targeted genetic tool, deletion of the colony-stimulating Factor 1 receptor (CSF1R) macrophage super-enhancer FIRE (Csf1rΔFIRE), to specifically deplete microglia and define the role of microglia in the pathogenesis of LS. Homozygosity for the Csf1rΔFIRE allele ablates microglia in both control and Ndufs4(-/-) animals, but onset of CNS lesions and sequalae in the Ndufs4(-/-), including mortality, are only marginally impacted by microglia depletion. The overall development of necrotizing CNS lesions is not altered, though microglia remain absent. Finally, histologic analysis of brainstem lesions provides direct evidence of a causal role for peripheral macrophages in the characteristic CNS lesions. These data demonstrate that peripheral macrophages play a key role in the pathogenesis of disease in the Ndufs4(-/-) model.
    Keywords:  CNS lesions; Leigh syndrome; microglia; mitochondrial disease; pediatric disease; subacute necrotizing encephalomyelopathy
    DOI:  https://doi.org/10.1111/bpa.13192
  23. Int J Mol Sci. 2023 Aug 06. pii: 12486. [Epub ahead of print]24(15):
    Exploring Molecular Targets for Mitochondrial Therapies in Neurodegenerative Diseases.
    Germán Plascencia-Villa, George Perry.
      The progressive deterioration of function and structure of brain cells in neurodegenerative diseases is accompanied by mitochondrial dysfunction, affecting cellular metabolism, intracellular signaling, cell differentiation, morphogenesis, and the activation of programmed cell death. However, most of the efforts to develop therapies for Alzheimer's and Parkinson's disease have focused on restoring or maintaining the neurotransmitters in affected neurons, removing abnormal protein aggregates through immunotherapies, or simply treating symptomatology. However, none of these approaches to treating neurodegeneration can stop or reverse the disease other than by helping to maintain mental function and manage behavioral symptoms. Here, we discuss alternative molecular targets for neurodegeneration treatments that focus on mitochondrial functions, including regulation of calcium ion (Ca2+) transport, protein modification, regulation of glucose metabolism, antioxidants, metal chelators, vitamin supplementation, and mitochondrial transference to compromised neurons. After pre-clinical evaluation and studies in animal models, some of these therapeutic compounds have advanced to clinical trials and are expected to have positive outcomes in subjects with neurodegeneration. These mitochondria-targeted therapeutic agents are an alternative to established or conventional molecular targets that have shown limited effectiveness in treating neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; mitochondria; mitochondrial dysfunction; neurodegeneration; neurons; oxidative stress
    DOI:  https://doi.org/10.3390/ijms241512486
  24. Mol Genet Metab. 2023 Aug 02. pii: S1096-7192(23)00306-2. [Epub ahead of print]140(3): 107676
    FGF21 and GDF15 are elevated in Barth Syndrome and are correlated to important clinical measures.
    Olivia Liu, Bhargava Kumar Chinni, Cedric Manlhiot, Hilary J Vernon.
      Barth Syndrome (BTHS) is a rare X-linked disorder that is caused by defects TAFAZZIN, which leads to an abnormal cardiolipin (CL) profile of the inner mitochondrial membrane and clinical features including cardiomyopathy, neutropenia and skeletal myopathy. The ratio of monolysocardiolipin (MLCL, the remodeling intermediate of cardiolipin) to remodeled CL is always abnormal in Barth Syndrome and 3-methylglutaconic acid is often elevated affected patients, however neither of these biomarkers has been shown to temporally correlate to clinical status. In this study, we measured plasma FGF21 and GDF15 levels in 16 individuals with Barth Syndrome and evaluated whether these biomarkers were correlated to the MLCL/CL ratio in patient bloodspots and clinical laboratory parameters indicative of organ involvement in Barth Syndrome including: neutrophil and monocyte counts, liver function, and cardiac function (NT-proBNP). We found that FGF21 and GDF15 were elevated in all 16 patients and that FGF21 was significantly correlated to AST, ALT GGT, percentage of neutrophils comprising total white blood cells, percent monocytes comprising total white blood cells, and NT-proBNP levels. GDF-15 was significantly positively associated with NT-proBNP. We conclude that clinical measurements of FGF21 and GDF-15 may be relevant in the monitoring multi-organ system involvement in Barth Syndrome.
    Keywords:  Barth Syndrome; Cardiolipin; FGF21; GDF-15; Mitochondria
    DOI:  https://doi.org/10.1016/j.ymgme.2023.107676
  25. Nat Cell Biol. 2023 Aug 10.
    Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor.
    Raffaele Nicastro, Laura Brohée, Josephine Alba, Julian Nüchel, Gianluca Figlia, Stefanie Kipschull, Peter Gollwitzer, Jesus Romero-Pozuelo, Stephanie A Fernandes, Andreas Lamprakis, Stefano Vanni, Aurelio A Teleman, Claudio De Virgilio, Constantinos Demetriades.
      Cell growth is regulated by the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which functions both as a nutrient sensor and a master controller of virtually all biosynthetic pathways. This ensures that cells are metabolically active only when conditions are optimal for growth. Notably, although mTORC1 is known to regulate fatty acid biosynthesis, how and whether the cellular lipid biosynthetic capacity signals back to fine-tune mTORC1 activity remains poorly understood. Here we show that mTORC1 senses the capacity of a cell to synthesise fatty acids by detecting the levels of malonyl-CoA, an intermediate of this biosynthetic pathway. We find that, in both yeast and mammalian cells, this regulation is direct, with malonyl-CoA binding to the mTOR catalytic pocket and acting as a specific ATP-competitive inhibitor. When fatty acid synthase (FASN) is downregulated/inhibited, elevated malonyl-CoA levels are channelled to proximal mTOR molecules that form direct protein-protein interactions with acetyl-CoA carboxylase 1 (ACC1) and FASN. Our findings represent a conserved and unique homeostatic mechanism whereby impaired fatty acid biogenesis leads to reduced mTORC1 activity to coordinately link this metabolic pathway to the overall cellular biosynthetic output. Moreover, they reveal the existence of a physiological metabolite that directly inhibits the activity of a signalling kinase in mammalian cells by competing with ATP for binding.
    DOI:  https://doi.org/10.1038/s41556-023-01198-6
  26. Curr Opin Struct Biol. 2023 Aug 03. pii: S0959-440X(23)00146-X. [Epub ahead of print]82 102672
    Molecular insights into the catalysis and regulation of mammalian NAD-dependent isocitrate dehydrogenases.
    Xingchen Chen, Jianping Ding.
      Eukaryotic NAD-dependent isocitrate dehydrogenases (NAD-IDHs) are mitochondria-localized enzymes which catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate using NAD as a cofactor. In mammals, NAD-IDHs (or IDH3) consist of three types of subunits (α, β, and γ), and exist as (α2βγ)2 heterooctamer. Mammalian NAD-IDHs are regulated allosterically and/or competitively by a diversity of metabolites including citrate, ADP, ATP, NADH, and NADPH, which are associated with cellular metabolite flux, energy demands, and redox status. Proper assembly of the component subunits is essential for the catalysis and regulation of the enzymes. Recently, crystal structures of human IDH3 have been solved in apo form and in complex with various ligands, revealing the molecular mechanisms for the assembly, catalysis, and regulation of the enzyme.
    DOI:  https://doi.org/10.1016/j.sbi.2023.102672
  27. Nature. 2023 Aug 09.
    Mitochondrial integrated stress response controls lung epithelial cell fate.
    SeungHye Han, Minho Lee, Youngjin Shin, Regina Giovanni, Ram P Chakrabarty, Mariana M Herrerias, Laura A Dada, Annette S Flozak, Paul A Reyfman, Basil Khuder, Colleen R Reczek, Lin Gao, José Lopéz-Barneo, Cara J Gottardi, G R Scott Budinger, Navdeep S Chandel.
      Alveolar epithelial type 1 (AT1) cells are necessary to transfer oxygen and carbon dioxide between the blood and air. Alveolar epithelial type 2 (AT2) cells serve as a partially committed stem cell population, producing AT1 cells during postnatal alveolar development and repair after influenza A and SARS-CoV-2 pneumonia1-6. Little is known about the metabolic regulation of the fate of lung epithelial cells. Here we report that deleting the mitochondrial electron transport chain complex I subunit Ndufs2 in lung epithelial cells during mouse gestation led to death during postnatal alveolar development. Affected mice displayed hypertrophic cells with AT2 and AT1 cell features, known as transitional cells. Mammalian mitochondrial complex I, comprising 45 subunits, regenerates NAD+ and pumps protons. Conditional expression of yeast NADH dehydrogenase (NDI1) protein that regenerates NAD+ without proton pumping7,8 was sufficient to correct abnormal alveolar development and avert lethality. Single-cell RNA sequencing revealed enrichment of integrated stress response (ISR) genes in transitional cells. Administering an ISR inhibitor9,10 or NAD+ precursor reduced ISR gene signatures in epithelial cells and partially rescued lethality in the absence of mitochondrial complex I function. Notably, lung epithelial-specific loss of mitochondrial electron transport chain complex II subunit Sdhd, which maintains NAD+ regeneration, did not trigger high ISR activation or lethality. These findings highlight an unanticipated requirement for mitochondrial complex I-dependent NAD+ regeneration in directing cell fate during postnatal alveolar development by preventing pathological ISR induction.
    DOI:  https://doi.org/10.1038/s41586-023-06423-8
  28. Nat Commun. 2023 08 05. 14(1): 4713
    Molecular basis of Mg2+ permeation through the human mitochondrial Mrs2 channel.
    Ming Li, Yang Li, Yue Lu, Jianhui Li, Xuhang Lu, Yue Ren, Tianlei Wen, Yaojie Wang, Shenghai Chang, Xing Zhang, Xue Yang, Yuequan Shen.
      Mitochondrial RNA splicing 2 (Mrs2), a eukaryotic CorA ortholog, enables Mg2+ to permeate the inner mitochondrial membrane and plays an important role in mitochondrial metabolic function. However, the mechanism by which Mrs2 permeates Mg2+ remains unclear. Here, we report four cryo-electron microscopy (cryo-EM) reconstructions of Homo sapiens Mrs2 (hMrs2) under various conditions. All of these hMrs2 structures form symmetrical pentamers with very similar pentamer and protomer conformations. A special structural feature of Cl--bound R-ring, which consists of five Arg332 residues, was found in the hMrs2 structure. Molecular dynamics simulations and mitochondrial Mg2+ uptake assays show that the R-ring may function as a charge repulsion barrier, and Cl- may function as a ferry to jointly gate Mg2+ permeation in hMrs2. In addition, the membrane potential is likely to be the driving force for Mg2+ permeation. Our results provide insights into the channel assembly and Mg2+ permeation of hMrs2.
    DOI:  https://doi.org/10.1038/s41467-023-40516-2
  29. Nat Struct Mol Biol. 2023 Aug 07.
    DELE1 oligomerization promotes integrated stress response activation.
    Jie Yang, Kelsey R Baron, Daniel E Pride, Anette Schneemann, Xiaoyan Guo, Wenqian Chen, Albert S Song, Giovanni Aviles, Martin Kampmann, R Luke Wiseman, Gabriel C Lander.
      Mitochondria are dynamic organelles that continually respond to cellular stress. Recent studies have demonstrated that mitochondrial stress is relayed from mitochondria to the cytosol by the release of a proteolytic fragment of DELE1 that binds to the eIF2α kinase HRI to initiate integrated stress response (ISR) signaling. We report the cryo-electron microscopy structure of the C-terminal cleavage product of human DELE1, which assembles into a high-order oligomer. The oligomer consists of eight DELE1 monomers that assemble with D4 symmetry via two sets of hydrophobic inter-subunit interactions. We identified the key residues involved in DELE1 oligomerization, and confirmed their role in stabilizing the octamer in vitro and in cells using mutagenesis. We further show that assembly-impaired DELE1 mutants are compromised in their ability to induce HRI-dependent ISR activation in cell culture models. Together, our findings provide molecular insights into the activity of DELE1 and how it signals to promote ISR activity following mitochondrial insult.
    DOI:  https://doi.org/10.1038/s41594-023-01061-0
  30. J Med Genet. 2023 Aug 09. pii: jmg-2023-109362. [Epub ahead of print]
    Use of genome sequencing to hunt for cryptic second-hit variants: analysis of 31 cases recruited to the 100 000 Genomes Project.
    Genomics England Research Consortium
       BACKGROUND: Current clinical testing methods used to uncover the genetic basis of rare disease have inherent limitations, which can lead to causative pathogenic variants being missed. Within the rare disease arm of the 100 000 Genomes Project (100kGP), families were recruited under the clinical indication 'single autosomal recessive mutation in rare disease'. These participants presented with strong clinical suspicion for a specific autosomal recessive disorder, but only one suspected pathogenic variant had been identified through standard-of-care testing. Whole genome sequencing (WGS) aimed to identify cryptic 'second-hit' variants.
    METHODS: To investigate the 31 families with available data that remained unsolved following formal review within the 100kGP, SVRare was used to aggregate structural variants present in <1% of 100kGP participants. Small variants were assessed using population allele frequency data and SpliceAI. Literature searches and publicly available online tools were used for further annotation of pathogenicity.
    RESULTS: Using these strategies, 8/31 cases were solved, increasing the overall diagnostic yield of this cohort from 10/41 (24.4%) to 18/41 (43.9%). Exemplar cases include a patient with cystic fibrosis harbouring a novel exonic LINE1 insertion in CFTR and a patient with generalised arterial calcification of infancy with complex interlinked duplications involving exons 2-6 of ENPP1. Although ambiguous by short-read WGS, the ENPP1 variant structure was resolved using optical genome mapping and RNA analysis.
    CONCLUSION: Systematic examination of cryptic variants across a multi-disease cohort successfully identifies additional pathogenic variants. WGS data analysis in autosomal recessive rare disease should consider complex structural and small intronic variants as potentially pathogenic second hits.
    Keywords:  diagnosis; genetic diseases, inborn; genetics, medical; genomics; sequence analysis, DNA
    DOI:  https://doi.org/10.1136/jmg-2023-109362
  31. bioRxiv. 2023 Jul 24. pii: 2023.07.21.550097. [Epub ahead of print]
    Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling.
    Nydia P Chang, Evan M DaPrano, Wesley R Evans, Marialaina Nissenbaum, Micheal McCourt, Diego Alzate, Marissa Lindman, Tsui-Wen Chou, Colm Atkins, Alexander W Kusnecov, Rafiq Huda, Brian P Daniels.
      Astrocyte activation is a common feature of neurodegenerative diseases. However, the ways in which dying neurons influence the activity of astrocytes is poorly understood. RIPK3 signaling has recently been described as a key regulator of neuroinflammation, but whether this kinase mediates astrocytic responsiveness to neuronal death has not yet been studied. Here, we used the MPTP model of Parkinson's disease to show that activation of astrocytic RIPK3 drives dopaminergic cell death and axon damage. Transcriptomic profiling revealed that astrocytic RIPK3 promoted gene expression associated with neuroinflammation and movement disorders, and this coincided with significant engagement of DAMP signaling. Using human cell culture systems, we show that factors released from dying neurons signal through RAGE to induce RIPK3-dependent astrocyte activation. These findings highlight a mechanism of neuron-glia crosstalk in which neuronal death perpetuates further neurodegeneration by engaging inflammatory astrocyte activation via RIPK3.
    DOI:  https://doi.org/10.1101/2023.07.21.550097
  32. Genome Biol. 2023 08 07. 24(1): 182
    Cross-protein transfer learning substantially improves disease variant prediction.
    Milind Jagota, Chengzhong Ye, Carlos Albors, Ruchir Rastogi, Antoine Koehl, Nilah Ioannidis, Yun S Song.
       BACKGROUND: Genetic variation in the human genome is a major determinant of individual disease risk, but the vast majority of missense variants have unknown etiological effects. Here, we present a robust learning framework for leveraging saturation mutagenesis experiments to construct accurate computational predictors of proteome-wide missense variant pathogenicity.
    RESULTS: We train cross-protein transfer (CPT) models using deep mutational scanning (DMS) data from only five proteins and achieve state-of-the-art performance on clinical variant interpretation for unseen proteins across the human proteome. We also improve predictive accuracy on DMS data from held-out proteins. High sensitivity is crucial for clinical applications and our model CPT-1 particularly excels in this regime. For instance, at 95% sensitivity of detecting human disease variants annotated in ClinVar, CPT-1 improves specificity to 68%, from 27% for ESM-1v and 55% for EVE. Furthermore, for genes not used to train REVEL, a supervised method widely used by clinicians, we show that CPT-1 compares favorably with REVEL. Our framework combines predictive features derived from general protein sequence models, vertebrate sequence alignments, and AlphaFold structures, and it is adaptable to the future inclusion of other sources of information. We find that vertebrate alignments, albeit rather shallow with only 100 genomes, provide a strong signal for variant pathogenicity prediction that is complementary to recent deep learning-based models trained on massive amounts of protein sequence data. We release predictions for all possible missense variants in 90% of human genes.
    CONCLUSIONS: Our results demonstrate the utility of mutational scanning data for learning properties of variants that transfer to unseen proteins.
    DOI:  https://doi.org/10.1186/s13059-023-03024-6
  33. Nat Cell Biol. 2023 Aug 10.
    Malonyl-CoA links lipid metabolism to nutrient signalling by directly inhibiting mTORC1.
      
    DOI:  https://doi.org/10.1038/s41556-023-01206-9
  34. Int J Mol Sci. 2023 Aug 01. pii: 12295. [Epub ahead of print]24(15):
    The Reduction in the Mitochondrial Membrane Potential in Aging: The Role of the Mitochondrial Permeability Transition Pore.
    Hagai Rottenberg.
      It is widely reported that the mitochondrial membrane potential, ∆Ψm, is reduced in aging animals. It was recently suggested that the lower ∆Ψm in aged animals modulates mitochondrial bioenergetics and that this effect is a major cause of aging since artificially increased ∆Ψm in C. elegans increased lifespan. Here, I critically review studies that reported reduction in ∆Ψm in aged animals, including worms, and conclude that many of these observations are best interpreted as evidence that the fraction of depolarized mitochondria is increased in aged cells because of the enhanced activation of the mitochondrial permeability transition pore, mPTP. Activation of the voltage-gated mPTP depolarizes the mitochondria, inhibits oxidative phosphorylation, releases large amounts of calcium and mROS, and depletes cellular NAD+, thus accelerating degenerative diseases and aging. Since the inhibition of mPTP was shown to restore ∆Ψm and to retard aging, the reported lifespan extension by artificially generated ∆Ψm in C. elegans is best explained by inhibition of the voltage-gated mPTP. Similarly, the reported activation of the mitochondrial unfolded protein response by reduction in ∆Ψm and the reported preservation of ∆Ψm in dietary restriction treatment in C. elegans are best explained as resulting from activation or inhibition of the voltage-gated mPTP, respectively.
    Keywords:  C. elegans; aging; membrane potential; mitochondria; permeability transition pore
    DOI:  https://doi.org/10.3390/ijms241512295
  35. Mol Med. 2023 Aug 09. 29(1): 107
    Polymorphic variants at NDUFC2, encoding a mitochondrial complex I subunit, associate with cardiac hypertrophy in human hypertension.
    Giovanna Gallo, Maurizio Forte, Maria Cotugno, Simona Marchitti, Rosita Stanzione, Giuliano Tocci, Franca Bianchi, Silvia Palmerio, Mariarosaria Scioli, Giacomo Frati, Sebastiano Sciarretta, Emanuele Barbato, Massimo Volpe, Speranza Rubattu.
       BACKGROUND: A dysfunction of NADH dehydrogenase, the mitochondrial Complex I (CI), associated with the development of left ventricular hypertrophy (LVH) in previous experimental studies. A deficiency of Ndufc2 (subunit of CI) impairs CI activity causing severe mitochondrial dysfunction. The T allele at NDUFC2/rs11237379 variant associates with reduced gene expression and impaired mitochondrial function. The present study tested the association of both NDUFC2/rs11237379 and NDUFC2/rs641836 variants with LVH in hypertensive patients. In vitro studies explored the impact of reduced Ndufc2 expression in isolated cardiomyocytes.
    METHODS: Two-hundred-forty-six subjects (147 male, 59.7%), with a mean age of 59 ± 15 years, were included for the genetic association analysis. Ndufc2 silencing was performed in both H9c2 and rat primary cardiomyocytes to explore the hypertrophy development and the underlying signaling pathway.
    RESULTS: The TT genotype at NDUFC2/rs11237379 associated with significantly reduced gene expression. Multivariate analysis revealed that patients carrying this genotype showed significant differences for septal thickness (p = 0.07), posterior wall thickness (p = 0.008), RWT (p = 0.021), LV mass/BSA (p = 0.03), compared to subjects carrying either CC or CT genotypes. Patients carrying the A allele at NDUFC2/rs641836 showed significant differences for septal thickness (p = 0.017), posterior wall thickness (p = 0.011), LV mass (p = 0.003), LV mass/BSA (p = 0.002) and LV mass/height2.7(p = 0.010) after adjustment for covariates. In-vitro, the Ndufc2 deficiency-dependent mitochondrial dysfunction caused cardiomyocyte hypertrophy, pointing to SIRT3-AMPK-AKT-MnSOD as a major underlying signaling pathway.
    CONCLUSIONS: We demonstrated for the first time a significant association of NDUFC2 variants with LVH in human hypertension and highlight a key role of Ndufc2 deficiency-dependent CI mitochondrial dysfunction on increased susceptibility to cardiac hypertrophy development.
    Keywords:  Cardiac hypertrophy; Hypertension; Mitochondrial complex I; Mitochondrial dysfunction; NDUFC2; SIRT3
    DOI:  https://doi.org/10.1186/s10020-023-00701-x
  36. Nat Genet. 2023 Aug 10.
    Genome-wide prediction of disease variant effects with a deep protein language model.
    Nadav Brandes, Grant Goldman, Charlotte H Wang, Chun Jimmie Ye, Vasilis Ntranos.
      Predicting the effects of coding variants is a major challenge. While recent deep-learning models have improved variant effect prediction accuracy, they cannot analyze all coding variants due to dependency on close homologs or software limitations. Here we developed a workflow using ESM1b, a 650-million-parameter protein language model, to predict all ~450 million possible missense variant effects in the human genome, and made all predictions available on a web portal. ESM1b outperformed existing methods in classifying ~150,000 ClinVar/HGMD missense variants as pathogenic or benign and predicting measurements across 28 deep mutational scan datasets. We further annotated ~2 million variants as damaging only in specific protein isoforms, demonstrating the importance of considering all isoforms when predicting variant effects. Our approach also generalizes to more complex coding variants such as in-frame indels and stop-gains. Together, these results establish protein language models as an effective, accurate and general approach to predicting variant effects.
    DOI:  https://doi.org/10.1038/s41588-023-01465-0
  37. Rev Endocr Metab Disord. 2023 Aug 10.
    White adipose tissue mitochondrial bioenergetics in metabolic diseases.
    Rugivan Sabaratnam, Didde Riisager Hansen, Per Svenningsen.
      White adipose tissue (WAT) is an important endocrine organ that regulates systemic energy metabolism. In metabolically unhealthy obesity, adipocytes become dysfunctional through hypertrophic mechanisms associated with a reduced endocrine function, reduced mitochondrial function, but increased inflammation, fibrosis, and extracellular remodelling. A pathologic WAT remodelling promotes systemic lipotoxicity characterized by fat accumulation in tissues such as muscle and liver, leading to systemic insulin resistance and type 2 diabetes. Several lines of evidence from human and animal studies suggest a link between unhealthy obesity and adipocyte mitochondrial dysfunction, and interventions that improve mitochondrial function may reduce the risk of obesity-associated diseases. This review discusses the importance of mitochondrial function and metabolism in human adipocyte biology and intercellular communication mechanisms within WAT. Moreover, a selected interventional approach for better adipocyte mitochondrial metabolism in humans is reviewed. A greater understanding of mitochondrial bioenergetics in WAT might provide novel therapeutic opportunities to prevent or restore dysfunctional adipose tissue in obesity-associated diseases.
    Keywords:  Adipose tissue; Extracellular vesicles; Mitochondria; Obesity
    DOI:  https://doi.org/10.1007/s11154-023-09827-z
  38. Int J Mol Sci. 2023 Jul 27. pii: 12012. [Epub ahead of print]24(15):
    Mitochondrial Dysfunction Associated with mtDNA in Metabolic Syndrome and Obesity.
    Natalia Todosenko, Olga Khaziakhmatova, Vladimir Malashchenko, Kristina Yurova, Maria Bograya, Maria Beletskaya, Maria Vulf, Natalia Gazatova, Larisa Litvinova.
      Metabolic syndrome (MetS) is a precursor to the major health diseases associated with high mortality in industrialized countries: cardiovascular disease and diabetes. An important component of the pathogenesis of the metabolic syndrome is mitochondrial dysfunction, which is associated with tissue hypoxia, disruption of mitochondrial integrity, increased production of reactive oxygen species, and a decrease in ATP, leading to a chronic inflammatory state that affects tissues and organ systems. The mitochondrial AAA + protease Lon (Lonp1) has a broad spectrum of activities. In addition to its classical function (degradation of misfolded or damaged proteins), enzymatic activity (proteolysis, chaperone activity, mitochondrial DNA (mtDNA)binding) has been demonstrated. At the same time, the spectrum of Lonp1 activity extends to the regulation of cellular processes inside mitochondria, as well as outside mitochondria (nuclear localization). This mitochondrial protease with enzymatic activity may be a promising molecular target for the development of targeted therapy for MetS and its components. The aim of this review is to elucidate the role of mtDNA in the pathogenesis of metabolic syndrome and its components as a key component of mitochondrial dysfunction and to describe the promising and little-studied AAA + LonP1 protease as a potential target in metabolic disorders.
    Keywords:  metabolic syndrome; mitochondrial dysfunction; mitochondrial protease Lonp1; mtDNA; obesity
    DOI:  https://doi.org/10.3390/ijms241512012
  39. Acta Neuropathol Commun. 2023 Aug 11. 11(1): 131
    A novel ELOVL4 variant, L168S, causes early childhood-onset Spinocerebellar ataxia-34 and retinal dysfunction: a case report.
    Yeboah Kofi Gyening, Keren Boris, Mignot Cyril, Richard S Brush, Marie-Cécile Nassogne, Martin-Paul Agbaga.
      Spinocerebellar ataxia 34 (SCA34) is an autosomal dominant inherited disease characterized by age-related cerebellar degeneration and ataxia caused by mutations in the Elongation of Very Long Chain Fatty Acid-4 (ELOVL4) gene. The ELOVL4 enzyme catalyzes the biosynthesis of both very long chain saturated fatty acids (VLC-SFA) and very long chain polyunsaturated fatty acids (VLC-PUFA) that are important for neuronal, reproductive, and skin function. Several variants in ELOVL4 have been shown to cause different tissue-specific disorders including SCA34 with or without Erythrokeratodermia Variabilis (EKV), a skin condition characterized by dry, scaly skin, Autosomal Dominant Stargardt-Like Macular Dystrophy (STGD3), and seizures associated with neuro-ichthyotic disorders. What is puzzling is how different mutations in the same gene seem to cause different tissue-specific disorders. To date, no SCA34 patients have presented with both SCA34 and STGD3 pathology that is caused by ELOVL4 variants that cause truncation of ELOVL4. Here, we report a novel case of an early childhood onset and rapidly progressive cerebellar degeneration and retinal dysfunction in a Belgian-Italian girl who developed severe dysarthria and gait problems starting at about 3.5 years of age and progressed to immobility by 4.5 years of age. Brain magnetic resonance imaging (MRI) revealed progressive vermian, cerebellar, cortical atrophy, progressive corpus callosum slimming, and hot cross bun sign visible on the MRI. Ophthalmological examinations also revealed progressive macular dysfunction as measured by electroretinography. Using exome sequencing, we identified a novel heterozygous ELOVL4 variant, c.503 T > C (p. L168S) in the patient. To understand the enzymatic function of this novel ELOVL4 variant and how it alters the levels of VLC-PUFA and VLC-SFA biosynthesis to contribute to cerebellar and retinal dysfunction, we expressed wild-type ELOVL4 or the L168S ELOVL4 variant in cell culture and supplemented the cultures with VLC-PUFA or VLC-SFA precursors. We showed that the L168S ELOVL4 variant is deficient in the biosynthesis of VLC-SFA and VLC-PUFA. Our work suggests that differential depletion of these fatty acids may be a contributing factor to the pathogenic mechanism of SCA34 with or without EKV. Further studies will help further define how the different ELOVL4 variants cause different tissue-specific disorders with variable ages of onset.
    Keywords:  Autosomal dominant Stargardt-like macular dystrophy (STGD3); Elongation of very long chain fatty acids-4 (ELOVL4); Erythrokeratodermia variabilis (EKV); Spinocerebellar ataxia 34 (SCA34); Very long chain polyunsaturated fatty acid (VLC-PUFA); Very long chain saturated fatty acid (VLC-SFA)
    DOI:  https://doi.org/10.1186/s40478-023-01628-4
  40. Hum Genomics. 2023 08 08. 17(1): 73
    The application of long-read sequencing in clinical settings.
    Josephine B Oehler, Helen Wright, Zornitza Stark, Andrew J Mallett, Ulf Schmitz.
      Long-read DNA sequencing technologies have been rapidly evolving in recent years, and their ability to assess large and complex regions of the genome makes them ideal for clinical applications in molecular diagnosis and therapy selection, thereby providing a valuable tool for precision medicine. In the third-generation sequencing duopoly, Oxford Nanopore Technologies and Pacific Biosciences work towards increasing the accuracy, throughput, and portability of long-read sequencing methods while trying to keep costs low. These trades have made long-read sequencing an attractive tool for use in research and clinical settings. This article provides an overview of current clinical applications and limitations of long-read sequencing and explores its potential for point-of-care testing and health care in remote settings.
    DOI:  https://doi.org/10.1186/s40246-023-00522-3
  41. Genet Med. 2023 Aug 04. pii: S1098-3600(23)00961-9. [Epub ahead of print] 100948
    Exome and genome sequencing for rare genetic disease diagnosis: A scoping review and critical appraisal of clinical guidance documents produced by genetics professional organizations.
    Taila Hartley, Meredith K Gillespie, Ian D Graham, Robin Z Hayeems, Sheena Li, Margaret Sampson, Kym M Boycott, Beth K Potter.
       PURPOSE: Exome and genome sequencing have rapidly transitioned from research methods to widely used clinical tests for diagnosing rare genetic diseases. We sought to synthesize the topics covered and appraise the development processes of clinical guidance documents generated by genetics professional organizations.
    METHODS: We conducted a scoping review of guidance documents published since 2010, systematically identified in peer-reviewed and grey literature, using established methods and reporting guidelines. We coded verbatim recommendations by topic using content analysis and critically appraised documents using the Appraisal of Guidelines Research and Evaluation (AGREE) II tool.
    RESULTS: We identified 30 guidance documents produced by eight organizations (2012-2022), yielding 611 recommendations covering 21 topics. The most common topic related to findings beyond the primary testing indication. Mean AGREE II scores were low across all six quality domains; scores for items related to rigour of development were among the lowest. More recently published documents generally received higher scores.
    CONCLUSION: Guidance documents included a broad range of recommendations, but were of low quality, particularly in their rigour of development. Developers should consider using tools such as AGREE II and basing recommendations on living knowledge syntheses to improve guidance development in this evolving space.
    Keywords:  AGREE II; Clinical guidance documents; Exome sequencing; Genome sequencing; Rare disease; Scoping review
    DOI:  https://doi.org/10.1016/j.gim.2023.100948
  42. Nat Aging. 2023 Aug 10.
    Universal DNA methylation age across mammalian tissues.
    A T Lu, Z Fei, A Haghani, T R Robeck, J A Zoller, C Z Li, R Lowe, Q Yan, J Zhang, H Vu, J Ablaeva, V A Acosta-Rodriguez, D M Adams, J Almunia, A Aloysius, R Ardehali, A Arneson, C S Baker, G Banks, K Belov, N C Bennett, P Black, D T Blumstein, E K Bors, C E Breeze, R T Brooke, J L Brown, G G Carter, A Caulton, J M Cavin, L Chakrabarti, I Chatzistamou, H Chen, K Cheng, P Chiavellini, O W Choi, S M Clarke, L N Cooper, M L Cossette, J Day, J DeYoung, S DiRocco, C Dold, E E Ehmke, C K Emmons, S Emmrich, E Erbay, C Erlacher-Reid, C G Faulkes, S H Ferguson, C J Finno, J E Flower, J M Gaillard, E Garde, L Gerber, V N Gladyshev, V Gorbunova, R G Goya, M J Grant, C B Green, E N Hales, M B Hanson, D W Hart, M Haulena, K Herrick, A N Hogan, C J Hogg, T A Hore, T Huang, J C Izpisua Belmonte, A J Jasinska, G Jones, E Jourdain, O Kashpur, H Katcher, E Katsumata, V Kaza, H Kiaris, M S Kobor, P Kordowitzki, W R Koski, M Krützen, S B Kwon, B Larison, S G Lee, M Lehmann, J F Lemaitre, A J Levine, C Li, X Li, A R Lim, D T S Lin, D M Lindemann, T J Little, N Macoretta, D Maddox, C O Matkin, J A Mattison, M McClure, J Mergl, J J Meudt, G A Montano, K Mozhui, J Munshi-South, A Naderi, M Nagy, P Narayan, P W Nathanielsz, N B Nguyen, C Niehrs, J K O'Brien, P O'Tierney Ginn, D T Odom, A G Ophir, S Osborn, E A Ostrander, K M Parsons, K C Paul, M Pellegrini, K J Peters, A B Pedersen, J L Petersen, D W Pietersen, G M Pinho, J Plassais, J R Poganik, N A Prado, P Reddy, B Rey, B R Ritz, J Robbins, M Rodriguez, J Russell, E Rydkina, L L Sailer, A B Salmon, A Sanghavi, K M Schachtschneider, D Schmitt, T Schmitt, L Schomacher, L B Schook, K E Sears, A W Seifert, A Seluanov, A B A Shafer, D Shanmuganayagam, A V Shindyapina, M Simmons, K Singh, I Sinha, J Slone, R G Snell, E Soltanmaohammadi, M L Spangler, M C Spriggs, L Staggs, N Stedman, K J Steinman, D T Stewart, V J Sugrue, B Szladovits, J S Takahashi, M Takasugi, E C Teeling, M J Thompson, B Van Bonn, S C Vernes, D Villar, H V Vinters, M C Wallingford, N Wang, R K Wayne, G S Wilkinson, C K Williams, R W Williams, X W Yang, M Yao, B G Young, B Zhang, Z Zhang, P Zhao, Y Zhao, W Zhou, J Zimmermann, J Ernst, K Raj, S Horvath.
      Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.
    DOI:  https://doi.org/10.1038/s43587-023-00462-6
  43. Pediatr Res. 2023 Aug 10.
    Genetic etiology of progressive pediatric neurological disorders.
    Juho Aaltio, Anna Etula, Simo Ojanen, Virginia Brilhante, Tuula Lönnqvist, Pirjo Isohanni, Anu Suomalainen.
       BACKGROUND: The aim of the study was to characterize molecular diagnoses in patients with childhood-onset progressive neurological disorders of suspected genetic etiology.
    METHODS: We studied 48 probands (age range from newborn to 17 years old) with progressive neurological disorders of unknown etiology from the largest pediatric neurology clinic in Finland. Phenotypes included encephalopathy (54%), neuromuscular disorders (33%), movement disorders (11%), and one patient (2%) with hemiplegic migraine. All patients underwent whole-exome sequencing and disease-causing genes were analyzed.
    RESULTS: We found 20 (42%) of the patients to have variants in genes previously associated with disease. Of these, 12 were previously reported disease-causing variants, whereas eight patients had a novel variant on a disease-causing gene: ATP7A, CHD2, PURA, PYCR2, SLC1A4, SPAST, TRIT1, and UPF3B. Genetics also enabled us to define atypical clinical presentations of Rett syndrome (MECP2) and Menkes disease (ATP7A). Except for one deletion, all findings were single-nucleotide variants (missense 72%, truncating 22%, splice-site 6%). Nearly half of the variants were de novo.
    CONCLUSIONS: The most common cause of childhood encephalopathies are de novo variants. Whole-exome sequencing, even singleton, proved to be an efficient tool to gain specific diagnoses and in finding de novo variants in a clinically heterogeneous group of childhood encephalopathies.
    IMPACT: Whole-exome sequencing is useful in heterogeneous pediatric neurology cohorts. Our article provides further evidence for and novel variants in several genes. De novo variants are an important cause of childhood encephalopathies.
    DOI:  https://doi.org/10.1038/s41390-023-02767-z
  44. Front Genet. 2023 ;14 1235887
    Case report: Asp194Ala variant in MFN2 is associated with ALS-FTD in an Italian family.
    C Vinciguerra, A Di Fonzo, E Monfrini, D Ronchi, S Cuoco, G Piscosquito, P Barone, M T Pellecchia.
      Background:MFN2 gene encodes the protein Mitofusin 2, involved in essential mitochondrial functions such as fusion, trafficking, turnover, and cellular interactions. We describe a family carrying a novel MFN2 mutation associated with ALS-frontotemporal dementia (FTD) clinical phenotype in the mother and Charcot-Marie-Tooth disease type 2A (CMT2A) in her son. Case presentation: The mother, a 67-year-old woman, referred to us for a three year-history of mood disturbance and gait impairment, and a more recent hypophonia, dysarthria, dysphagia, and diffuse muscle wasting. Family history was positive for psychiatric disorders and gait disturbances. Brain 18F-FDG PET showed severe hypometabolism in the fronto-temporal brain cortex bilaterally. Electrodiagnostic studies (EDX) showed severe motor axonopathy in the bulbar, cervical and lumbosacral districts. Her 41-year-old son had a history of mood depression and sensory disturbances in the limbs, along with mild muscle wasting, weakness, and reduced reflexes. Nerve conduction studies revealed a moderate sensory-motor polyneuropathy, while brain MRI was normal. Whole exome sequencing of the patients' DNA identified the novel MFN2 (NM_014874.4) variant c.581A>C p.(Asp194Ala). Conclusion: Our findings provide evidence of heterogenous clinical manifestations in family members sharing the same MFN2 molecular defect. Additionally, we present the first documented case of ASL-FTD associated with an MFN2 mutation, thereby expanding the range of MFN-related disorders. Further research involving larger cohorts of patients will be needed to better understand the role of MFN2 as a contributing gene in the development of ALS-FTD.
    Keywords:  amyotrophic lateral sclerosis (ALS); charcot marie tooth (CMT); frontotemporal dementia (FTD); mitofusin 2-gene (MFN2); whole exom sequencing
    DOI:  https://doi.org/10.3389/fgene.2023.1235887
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