bims-mitmed 2024-05-19 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2024‒05‒19
thirty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

A novel MT-ATP6 variant associated with complicated ataxia in two unrelated Italian patients: case report and functional studies.
The Blood-Brain Barrier Is Unaffected in the Ndufs4-/- Mouse Model of Leigh Syndrome.
Mitochondrial heterogeneity and adaptations to cellular needs.
Glial overexpression of Tspo extends lifespan and protects against frataxin deficiency in Drosophila.
Editorial: Molecular links between mitochondrial damage and human neurodegenerative disorders, volume II.
Deoxyguanosine kinase deficiency: natural history and liver transplant outcome.
Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay.
SIN-3 transcriptional coregulator maintains mitochondrial homeostasis and polyamine flux.
Increased Diagnostic Yield by Reanalysis of Whole Exome Sequencing Data in Mitochondrial Disease.
Human embryos embrace asymmetry to form the body.
Mitochondrial Biomarkers in the Omics Era: A Clinical-Pathophysiological Perspective.
The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration.
Leber's hereditary optic neuropathy like disease in MT-ATP6 variant m.8969G>A.
Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission.
Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY-associated diseases.
Mitochondrial cardiomyopathy: a puzzle for the final diagnosis.
PGC-1α integrates insulin signaling with mitochondrial physiology and behavior in a Drosophila model of Fragile X Syndrome.
Mitochondrial DNA Missense Mutations ChrMT: 8981A > G and ChrMT: 6268C > T Identified in a Caucasian Female with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Triggered by the Epstein-Barr Virus.
Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes.
Lack of compensatory mitophagy in skeletal muscles during sepsis.
Mitochondrial function and gastrointestinal diseases.
Mitochondria-Derived Vesicles, Sterile Inflammation, and Pyroptosis in Liver Cancer: Partners in Crime or Innocent Bystanders?
Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE.
Pig-organ transplants: what three human recipients have taught scientists.
A current view of mitochondria damage and the diversity of lipopigment inclusions in neuronal ceroid lipofuscinose type 2 from rectal biopsy.
Mitophagy in health and disease. Molecular mechanisms, regulatory pathways, and therapeutic implications.
Atypical Late-Onset Leber Hereditary Optic Neuropathy (LHON) Associated With T14484C Mutation.
Dynamics of cognitive variability with age and its genetic underpinning in NIHR BioResource Genes and Cognition cohort participants.
AMPK as a mediator of tissue preservation: time for a shift in dogma?
Characterization of clinical serum cardiac biomarker levels in individuals with Friedreich ataxia.
The first two blastomeres contribute unequally to the human embryo.
Friedreich Ataxia Caregiver-Reported Health Index: Development of a Novel, Disease-Specific Caregiver-Reported Outcome Measure.

Orphanet J Rare Dis. 2024 May 16. 19(1): 200

A novel MT-ATP6 variant associated with complicated ataxia in two unrelated Italian patients: case report and functional studies.

Daniele Sala, Silvia Marchet, Lorenzo Nanetti, Andrea Legati, Caterina Mariotti, Eleonora Lamantea, Daniele Ghezzi, Alessia Catania, Costanza Lamperti.

  BACKGROUND: MT-ATP6 is a mitochondrial gene which encodes for the intramembrane subunit 6 (or A) of the mitochondrial ATP synthase, also known asl complex V, which is involved in the last step of oxidative phosphorylation to produce cellular ATP through aerobic metabolism. Although classically associated with the NARP syndrome, recent evidence highlights an important role of MT-ATP6 pathogenic variants in complicated adult-onset ataxias.METHODS: We describe two unrelated patients with adult-onset cerebellar ataxia associated with severe optic atrophy and mild cognitive impairment. Whole mitochondrial DNA sequencing was performed in both patients. We employed patients' primary fibroblasts and cytoplasmic hybrids (cybrids), generated from patients-derived cells, to assess the activity of respiratory chain complexes, oxygen consumption rate (OCR), ATP production and mitochondrial membrane potential.
RESULTS: In both patients, we identified the same novel m.8777 T > C variant in MT-ATP6 with variable heteroplasmy level in different tissues. We identifed an additional heteroplasmic novel variant in MT-ATP6, m.8879G > T, in the patients with the most severe phenotype. A significant reduction in complex V activity, OCR and ATP production was observed in cybrid clones homoplasmic for the m.8777 T > C variant, while no functional defect was detected in m.8879G > T homoplasmic clones. In addition, fibroblasts with high heteroplasmic levelsof m.8777 T > C variant showed hyperpolarization of mitochondrial membranes.
CONCLUSIONS: We describe a novel pathogenic mtDNA variant in MT-ATP6 associated with adult-onset ataxia, reinforcing the value of mtDNA screening within the diagnostic workflow of selected patients with late onset ataxias.

Keywords:   MT-ATP6 ; ATP synthase; Ataxia; Complex V; Cybrids; Mitochondria; OXPHOS; Oxygen consumption

DOI:  https://doi.org/10.1186/s13023-024-03212-y
Int J Mol Sci. 2024 Apr 29. pii: 4828. [Epub ahead of print]25(9):

The Blood-Brain Barrier Is Unaffected in the Ndufs4-/- Mouse Model of Leigh Syndrome.

Robin Reynaud-Dulaurier, Romain Clément, Sara Yjjou, Cassandra Cresson, Yasmina Saoudi, Mathilde Faideau, Michael Decressac.

  Mitochondrial dysfunction plays a major role in physiological aging and in many pathological conditions. Yet, no study has explored the consequence of primary mitochondrial deficiency on the blood-brain barrier (BBB) structure and function. Addressing this question has major implications for pharmacological and genetic strategies aimed at ameliorating the neurological symptoms that are often predominant in patients suffering from these conditions. In this study, we examined the permeability of the BBB in the Ndufs4-/- mouse model of Leigh syndrome (LS). Our results indicated that the structural and functional integrity of the BBB was preserved in this severe model of mitochondrial disease. Our findings suggests that pharmacological or gene therapy strategies targeting the central nervous system in this mouse model and possibly other models of mitochondrial dysfunction require the use of specific tools to bypass the BBB. In addition, they raise the need for testing the integrity of the BBB in complementary in vivo models.

Keywords:  AAV vector; Leigh syndrome; blood–brain barrier; mitochondrial diseases

DOI:  https://doi.org/10.3390/ijms25094828
Nat Cell Biol. 2024 May;26(5): 674-686

Mitochondrial heterogeneity and adaptations to cellular needs.

Melia Granath-Panelo, Shingo Kajimura.

Although it is well described that mitochondria are at the epicentre of the energy demands of a cell, it is becoming important to consider how each cell tailors its mitochondrial composition and functions to suit its particular needs beyond ATP production. Here we provide insight into mitochondrial heterogeneity throughout development as well as in tissues with specific energy demands and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling.

DOI: https://doi.org/10.1038/s41556-024-01410-1
Biochimie. 2024 May 13. pii: S0300-9084(24)00097-X. [Epub ahead of print]

Glial overexpression of Tspo extends lifespan and protects against frataxin deficiency in Drosophila.

Estelle Jullian, Maria Russi, Ema Turki, Margaux Bouvelot, Laura Tixier, Sandrine Middendorp, Elodie Martin, Véronique Monnier.

  The translocator protein TSPO is an evolutionary conserved mitochondrial protein overexpressed in various contexts of neurodegeneration. Friedreich Ataxia (FA) is a neurodegenerative disease due to GAA expansions in the FXN gene leading to decreased expression of frataxin, a mitochondrial protein involved in the biosynthesis of iron-sulfur clusters. We previously reported that Tspo was overexpressed in a Drosophila model of this disease generated by CRISPR/Cas9 insertion of approximately 200 GAA in the intron of fh, the fly frataxin gene. Here, we describe a new Drosophila model of FA with 42 GAA repeats, called fh-GAAs. The smaller expansion size allowed to obtain adults exhibiting hallmarks of the FA disease, including short lifespan, locomotory defects and hypersensitivity to oxidative stress. The reduced lifespan was fully rescued by ubiquitous expression of human FXN, confirming that both frataxins share conserved functions. We observed that Tspo was overexpressed in heads and decreased in intestines of these fh-GAAs flies. Then, we further overexpressed Tspo specifically in glial cells and observed improved survival. Finally, we investigated the effects of Tspo overexpression in healthy flies. Increased longevity was conferred by glial-specific overexpression, with opposite effects in neurons. Overall, this study highlights protective effects of glial TSPO in Drosophila both in a neurodegenerative and a healthy context.

Keywords:  Drosophila; Friedreich ataxia; TSPO; frataxin; glia; longevity

DOI:  https://doi.org/10.1016/j.biochi.2024.05.003
Front Cell Dev Biol. 2024 ;12 1417802

Editorial: Molecular links between mitochondrial damage and human neurodegenerative disorders, volume II.

Yuzuru Imai.



Keywords:  CHCHD10; CHCHD2; FMR1; Parkin (PARK2); fragile X syndrome; mitochondria; mitophagy; mtDNA

DOI:  https://doi.org/10.3389/fcell.2024.1417802
Brain Commun. 2024 ;6(3): fcae160

Deoxyguanosine kinase deficiency: natural history and liver transplant outcome.

Eleonora Manzoni, Sara Carli, Pauline Gaignard, Lea Dewi Schlieben, Michio Hirano, Dario Ronchi, Emmanuel Gonzales, Masaru Shimura, Kei Murayama, Yasushi Okazaki, Ivo Barić, Danijela Petkovic Ramadza, Daniela Karall, Johannes Mayr, Diego Martinelli, Chiara La Morgia, Guido Primiano, René Santer, Serenella Servidei, Céline Bris, Aline Cano, Francesca Furlan, Serena Gasperini, Nolwenn Laborde, Costanza Lamperti, Dominic Lenz, Michelangelo Mancuso, Vincenzo Montano, Francesca Menni, Olimpia Musumeci, Victoria Nesbitt, Elena Procopio, Cécile Rouzier, Christian Staufner, Jan-Willem Taanman, Galit Tal, Chiara Ticci, Duccio Maria Cordelli, Valerio Carelli, Vincent Procaccio, Holger Prokisch, Caterina Garone.

  Autosomal recessive pathogenetic variants in the DGUOK gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological involvement and a clinical course rapidly progressing to death. This is an international multicentre study aiming to provide a retrospective natural history of deoxyguanosine kinase deficient patients. A systematic literature review from January 2001 to June 2023 was conducted. Physicians of research centres or clinicians all around the world caring for previously reported patients were contacted to provide followup information or additional clinical, biochemical, histological/histochemical, and molecular genetics data for unreported cases with a confirmed molecular diagnosis of deoxyguanosine kinase deficiency. A cohort of 202 genetically confirmed patients, 36 unreported, and 166 from a systematic literature review, were analyzed. Patients had a neonatal onset (≤ 1 month) in 55.7% of cases, infantile (>1 month and ≤ 1 year) in 32.3%, pediatric (>1 year and ≤18 years) in 2.5% and adult (>18 years) in 9.5%. Kaplan-Meier analysis showed statistically different survival rates (P < 0.0001) among the four age groups with the highest mortality for neonatal onset. Based on the clinical phenotype, we defined four different clinical subtypes: hepatocerebral (58.8%), isolated hepatopathy (21.9%), hepatomyoencephalopathy (9.6%), and isolated myopathy (9.6%). Muscle involvement was predominant in adult-onset cases whereas liver dysfunction causes morbidity and mortality in early-onset patients with a median survival of less than 1 year. No genotype-phenotype correlation was identified. Liver transplant significantly modified the survival rate in 26 treated patients when compared with untreated. Only six patients had additional mild neurological signs after liver transplant. In conclusion, deoxyguanosine kinase deficiency is a disease spectrum with a prevalent liver and brain tissue specificity in neonatal and infantile-onset patients and muscle tissue specificity in adult-onset cases. Our study provides clinical, molecular genetics and biochemical data for early diagnosis, clinical trial planning and immediate intervention with liver transplant and/or nucleoside supplementation.

Keywords:  DGUOK; deoxyguanosine kinase; liver transplant; mitochondrial DNA; nucleosides

DOI:  https://doi.org/10.1093/braincomms/fcae160
Cerebellum. 2024 May 13.

Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay.

Chunling Chen, Ronald A Merrill, Chian Ju Jong, Stefan Strack.

  Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the SACS gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with Sacs knock-out (KO) mice and patient-derived fibroblasts suggested that SACSIN mutations inhibit the function of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction. We experimentally tested this hypothesis by genetically manipulating the mitochondrial fission/fusion equilibrium, creating double KO (DKO) mice that also lack positive (PP2A/Bβ2) and negative (PKA/AKAP1) regulators of Drp1. Neither promoting mitochondrial fusion (Bβ2 KO) nor fission (Akap1 KO) influenced progression of motor symptoms in Sacs KO mice. However, our studies identified profound learning and memory deficits in aged Sacs KO mice. Moreover, this cognitive impairment was rescued in a gene dose-dependent manner by deletion of the Drp1 inhibitor PKA/Akap1. Our results are inconsistent with mitochondrial dysfunction as a primary pathogenic mechanism in ARSACS. Instead, they imply that promoting mitochondrial fission may be beneficial at later stages of the disease when pathology extends to brain regions subserving learning and memory.

Keywords:  A kinase anchoring protein; ARSACS; Ataxia; Dynamin-related protein 1; Mitochondrial dynamics; Protein phosphatase 2A

DOI:  https://doi.org/10.1007/s12311-024-01701-1
iScience. 2024 May 17. 27(5): 109789

SIN-3 transcriptional coregulator maintains mitochondrial homeostasis and polyamine flux.

Giovannetti Marina, Rodríguez-Palero María-Jesús, Fabrizio Paola, Nicolle Ophélie, Bedet Cécile, Michaux Grégoire, Witting Michael, Artal-Sanz Marta, Palladino Francesca.

  Mitochondrial function relies on the coordinated transcription of mitochondrial and nuclear genomes to assemble respiratory chain complexes. Across species, the SIN3 coregulator influences mitochondrial functions, but how its loss impacts mitochondrial homeostasis and metabolism in the context of a whole organism is unknown. Exploring this link is important because SIN3 haploinsufficiency causes intellectual disability/autism syndromes and SIN3 plays a role in tumor biology. Here we show that loss of C. elegans SIN-3 results in transcriptional deregulation of mitochondrial- and nuclear-encoded mitochondrial genes, potentially leading to mito-nuclear imbalance. Consistent with impaired mitochondrial function, sin-3 mutants show extensive mitochondrial fragmentation by transmission electron microscopy (TEM) and in vivo imaging, and altered oxygen consumption. Metabolomic analysis of sin-3 mutant animals revealed a mitochondria stress signature and deregulation of methionine flux, resulting in decreased S-adenosyl methionine (SAM) and increased polyamine levels. Our results identify SIN3 as a key regulator of mitochondrial dynamics and metabolic flux, with important implications for human pathologies.

Keywords:  Cell biology; Omics; Systems biology

DOI:  https://doi.org/10.1016/j.isci.2024.109789
J Neuromuscul Dis. 2024 May 13.

Increased Diagnostic Yield by Reanalysis of Whole Exome Sequencing Data in Mitochondrial Disease.

Catarina Olimpio, Ida Paramonov, Leslie Matalonga, Steven Laurie, Katherine Schon, Kiran Polavarapu, Janbernd Kirschner, Ulrike Schara-Schmidt, Hanns Lochmüller, Patrick F Chinnery, Rita Horvath.

  Background: The genetic diagnosis of mitochondrial disorders is complicated by its genetic and phenotypic complexity. Next generation sequencing techniques have much improved the diagnostic yield for these conditions. A cohort of individuals with multiple respiratory chain deficiencies, reported in the literature 10 years ago, had a diagnostic rate of 60% by whole exome sequencing (WES) but 40% remained undiagnosed.Objective: We aimed to identify a genetic diagnosis by reanalysis of the WES data for the undiagnosed arm of this 10-year-old cohort of patients with suspected mitochondrial disorders.
Methods: The WES data was transferred and processed by the RD-Connect Genome-Phenome Analysis Platform (GPAP) using their standardized pipeline. Variant prioritisation was carried out on the RD-Connect GPAP.
Results: Singleton WES data from 14 individuals was reanalysed. We identified a possible or likely genetic diagnosis in 8 patients (8/14, 57%). The variants identified were in a combination of mitochondrial DNA (n = 1, MT-TN), nuclear encoded mitochondrial genes (n = 2, PDHA1, and SUCLA2) and nuclear genes associated with nonmitochondrial disorders (n = 5, PNPLA2, CDC40, NBAS and SLC7A7). Variants in both the NBAS and CDC40 genes were established as disease causing after the original cohort was published. We increased the diagnostic yield for the original cohort by 15% without generating any further genomic data.
CONCLUSIONS: In the era of multiomics we highlight that reanalysis of existing WES data is a valid tool for generating additional diagnosis in patients with suspected mitochondrial disease, particularly when more time has passed to allow for new bioinformatic pipelines to emerge, for the development of new tools in variant interpretation aiding in reclassification of variants and the expansion of scientific knowledge on additional genes.

Keywords:  Mitochondrial diseases; mitochondrial genes; next generation sequencing; respiratory chain deficiencies

DOI:  https://doi.org/10.3233/JND-240020
Nature. 2024 May 13.

Human embryos embrace asymmetry to form the body.

Sara Reardon.



Keywords:  Cell biology; Developmental biology; Medical research

DOI:  https://doi.org/10.1038/d41586-024-01403-y
Int J Mol Sci. 2024 Apr 29. pii: 4855. [Epub ahead of print]25(9):

Mitochondrial Biomarkers in the Omics Era: A Clinical-Pathophysiological Perspective.

Jacopo Gervasoni, Aniello Primiano, Michela Cicchinelli, Lavinia Santucci, Serenella Servidei, Andrea Urbani, Guido Primiano, Federica Iavarone.

  Mitochondrial diseases (MDs) affect 4300 individuals, with different ages of presentation and manifestation in any organ. How defects in mitochondria can cause such a diverse range of human diseases remains poorly understood. In recent years, several published research articles regarding the metabolic and protein profiles of these neurogenetic disorders have helped shed light on the pathogenetic mechanisms. By investigating different pathways in MDs, often with the aim of identifying disease biomarkers, it is possible to identify molecular processes underlying the disease. In this perspective, omics technologies such as proteomics and metabolomics considered in this review, can support unresolved mitochondrial questions, helping to improve outcomes for patients.

Keywords:  FTIR; LC-MS; biomarkers; metabolomics; mitochondrial diseases; personalized medicine; proteomics

DOI:  https://doi.org/10.3390/ijms25094855
Aging Cell. 2024 May 16. e14165

The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration.

Mohamed Ariff Iqbal, Maria Bilen, Yubing Liu, Vanessa Jabre, Bensun C Fong, Imane Chakroun, Smitha Paul, Jingwei Chen, Steven Wade, Michel Kanaan, Mary-Ellen Harper, Mireille Khacho, Ruth S Slack.

  Impaired mitochondrial function is a hallmark of aging and a major contributor to neurodegenerative diseases. We have shown that disrupted mitochondrial dynamics typically found in aging alters the fate of neural stem cells (NSCs) leading to impairments in learning and memory. At present, little is known regarding the mechanisms by which neural stem and progenitor cells survive and adapt to mitochondrial dysfunction. Using Opa1-inducible knockout as a model of aging and neurodegeneration, we identify a decline in neurogenesis due to impaired stem cell activation and progenitor proliferation, which can be rescued by the mitigation of oxidative stress through hypoxia. Through sc-RNA-seq, we identify the ATF4 pathway as a critical mechanism underlying cellular adaptation to metabolic stress. ATF4 knockdown in Opa1-deficient NSCs accelerates cell death, while the increased expression of ATF4 enhances proliferation and survival. Using a Slc7a11 mutant, an ATF4 target, we show that ATF4-mediated glutathione production plays a critical role in maintaining NSC survival and function under stress conditions. Together, we show that the activation of the integrated stress response (ISR) pathway enables NSCs to adapt to metabolic stress due to mitochondrial dysfunction and metabolic stress and may serve as a therapeutic target to enhance NSC survival and function in aging and neurodegeneration.

Keywords:  Hypoxia; Opa1; adult neurogenesis; intergrated stress response; metabolic adaptation; mitochondrial dynamics; neurodegeneration

DOI:  https://doi.org/10.1111/acel.14165
Am J Ophthalmol Case Rep. 2024 Jun;34 102070

Leber's hereditary optic neuropathy like disease in MT-ATP6 variant m.8969G>A.

Cansu de Muijnck, Mary J van Schooneveld, Astrid S Plomp, Richard J Rodenburg, Maria M van Genderen, Camiel J F Boon.

  Purpose: To describe a case with Leber's hereditary optic neuropathy (LHON) like optic atrophy in the presence of MT-ATP6 gene variant m.8969G > A.Observations: A 20-year-old patient with a history of mild developmental delay, mild cognitive impairment, and positional tremor presented with subacute painless visual loss over a few weeks. Mitochondrial genome sequencing revealed a variant in MT-ATP6, m.8969G > A (p.Ser148Asn). This variant was previously reported in association with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) and with nephropathy, followed by brain atrophy, muscle weakness and arrhythmias, but not with optic atrophy.
Conclusions and importance: Rare variants in MT-ATP6 can also cause LHON like optic atrophy. It is important to perform further genetic analysis of mitochondrial DNA in genetically unsolved cases suspected of Leber's hereditary optic neuropathy to confirm the clinical diagnosis.

Keywords:  Leber's hereditary optic neuropathy; MT-ATP6; Optic atrophy

DOI:  https://doi.org/10.1016/j.ajoc.2024.102070
iScience. 2024 May 17. 27(5): 109808

Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission.

Charlène Lhuissier, Valérie Desquiret-Dumas, Anaïs Girona, Jennifer Alban, Justine Faure, Julien Cassereau, Philippe Codron, Guy Lenaers, Olivier R Baris, Naïg Gueguen, Arnaud Chevrollier.

  Mitochondrial dynamics is a process that balances fusion and fission events, the latter providing a mechanism for segregating dysfunctional mitochondria. Fission is controlled by the mitochondrial membrane potential (ΔΨm), optic atrophy 1 (OPA1) cleavage, and DRP1 recruitment. It is thought that this process is closely linked to the activity of the mitochondrial respiratory chain (MRC). However, we report here that MRC inhibition does not decrease ΔΨm nor increase fission, as evidenced by hyperconnected mitochondria. Conversely, blocking F0F1-ATP synthase activity induces fragmentation. We show that the F0F1-ATP synthase is sensing the inhibition of MRC activity by immediately promoting its reverse mode of action to hydrolyze matrix ATP and restoring ΔΨm, thus preventing fission. While this reverse mode is expected to be inhibited by the ATPase inhibitor ATPIF1, we show that this sensing is independent of this factor. We have unraveled an unexpected role of F0F1-ATP synthase in controlling the induction of fission by sensing and maintaining ΔΨm.

Keywords:  Biochemistry; Cell biology; Functional aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2024.109808
Ann Clin Transl Neurol. 2024 May 15.

Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY-associated diseases.

Chiara Cavestro, Francesca Morra, Andrea Legati, Marco D'Amato, Alessia Nasca, Arcangela Iuso, Naomi Lubarr, Jennifer L Morrison, Patricia G Wheeler, Clara Serra-Juhé, Benjamín Rodríguez-Santiago, Eulalia Turón-Viñas, Clement Prouteau, Magalie Barth, Susan J Hayflick, Daniele Ghezzi, Valeria Tiranti, Ivano Di Meo.

OBJECTIVE: COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein-associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY-related disorders.METHODS: Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts.
RESULTS: We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY-related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4'-phosphopantetheinylated proteins were significantly reduced in COASY patients.
INTERPRETATION: These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY-associated diseases.

DOI: https://doi.org/10.1002/acn3.52079
Cardiol Young. 2024 May 16. 1-4

Mitochondrial cardiomyopathy: a puzzle for the final diagnosis.

Andreia Duarte Constante, Susana Martins Abreu, Conceição Trigo.

  Hypertrophic cardiomyopathy in children has diverse causes. Mitochondrial diseases, a rare aetiology leading to cardiomyopathy in 20-40% of affected children, predominantly present as hypertrophic cardiomyopathy. Diagnosis is challenging due to inconsistent genotype-phenotype correlation, resulting in various clinical presentations. We present a case of a one-month-old infant with severe hypertrophic cardiomyopathy and cardiac tamponade. Genetic diagnosis revealed a Valyl-tRNA synthetase 2 (VARS2) gene mutation, linking it to mitochondrial encephalopathy-cardiomyopathy. This case highlights novel variants and expands the understanding of hypertrophic cardiomyopathy aetiology in infants.

Keywords:  VARS2; hypertrophic cardiomyopathy; mitochondrial diseases

DOI:  https://doi.org/10.1017/S1047951124025095
NPJ Metab Health Dis. 2024 ;pii: 2. [Epub ahead of print]2

PGC-1α integrates insulin signaling with mitochondrial physiology and behavior in a Drosophila model of Fragile X Syndrome.

Eliana D Weisz, Adam R Fenton, Thomas A Jongens.

Fragile X Syndrome (FXS) is the most prevalent monogenetic form of intellectual disability and autism. Recently, dysregulation of insulin signaling (IS) and aberrations in mitochondrial function have emerged as robust, evolutionarily conserved components of FXS pathophysiology. However, the mechanisms by which altered IS and mitochondrial dysfunction impact behavior in the context of FXS remain elusive. Here, we show that normalization of IS improves mitochondrial volume and function in flies that lack expression of dfmr1, the Drosophila homolog of the causal gene of FXS in humans. Further, we demonstrate that dysregulation of IS underlies diminished expression of the mitochondrial master regulator PGC-1α/Spargel in dfmr1 mutant flies. These results are behaviorally relevant, as we show that pan-neuronal augmentation of PGC-1α/Spargel improves circadian behavior in dfmr1 mutants. Notably, we also show that modulation of PGC-1α/Spargel expression in wild-type flies phenocopies the dfmr1 mutant circadian defect. Taken together, the results presented herein provide a mechanistic link between mitochondrial function and circadian behavior both in FXS pathogenesis as well as more broadly at the interface between metabolism and behavioral output.

DOI: https://doi.org/10.1038/s44324-024-00004-7
Case Rep Genet. 2024 ;2024 6475425

Mitochondrial DNA Missense Mutations ChrMT: 8981A > G and ChrMT: 6268C > T Identified in a Caucasian Female with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Triggered by the Epstein-Barr Virus.

Gaoyan G Tang-Siegel, David W Maughan, Milah B Frownfelter, Alan R Light.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem disabling disease with unclear etiology and pathophysiology, whose typical symptoms include prolonged debilitating recovery from fatigue or postexertional malaise (PEM). Disrupted production of adenosine triphosphate (ATP), the intracellular energy that fuels cellular activity, is a cause for fatigue. Here, we present a long-term case of ME/CFS: a 75-year-old Caucasian female patient, whose symptoms of ME/CFS were clearly triggered by an acute infection of the Epstein-Barr virus 24 years ago (mononucleosis). Before then, the patient was a healthy professional woman. A recent DNA sequence analysis identified missense variants of mitochondrial respiratory chain enzymes, including ATP6 (ChrMT: 8981A > G; Q152R) and Cox1 (ChrMT: 6268C > T; A122V). Protein subunits ATP6 and Cox1 are encoded by mitochondrial DNA outside of the nucleus: the Cox1 gene encodes subunit 1 of complex IV (CIV: cytochrome c oxidase) and the ATP6 gene encodes subunit A of complex V (CV: ATP synthase). CIV and CV are the last two of five essential enzymes that perform the mitochondrial electron transport respiratory chain reaction to generate ATP. Further analysis of the blood sample using transmission electron microscopy demonstrated abnormal, circulating, extracellular mitochondria. These results indicate that the patient had dysfunctional mitochondria, which may contribute directly to her major symptoms, including PEM and neurological and cognitive changes. Furthermore, the identified variants of ATP6 (ChrMT: 8981A > G; Q152R) and Cox1 (ChrMT: 6268C > T; A122V), functioning at a later stage of mitochondrial ATP production, may play a role in the abnormality of the patient's mitochondria and the development of her ME/CFS symptoms.

DOI: https://doi.org/10.1155/2024/6475425
Nat Genet. 2024 May;56(5): 889-899

Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes.

Minsoo Kim, Alexander N Gorelick, Ignacio Vàzquez-García, Marc J Williams, Sohrab Salehi, Hongyu Shi, Adam C Weiner, Nick Ceglia, Tyler Funnell, Tricia Park, Sonia Boscenco, Ciara H O'Flanagan, Hui Jiang, Diljot Grewal, Cerise Tang, Nicole Rusk, Payam A Gammage, Andrew McPherson, Sam Aparicio, Sohrab P Shah, Ed Reznik.

The extent of cell-to-cell variation in tumor mitochondrial DNA (mtDNA) copy number and genotype, and the phenotypic and evolutionary consequences of such variation, are poorly characterized. Here we use amplification-free single-cell whole-genome sequencing (Direct Library Prep (DLP+)) to simultaneously assay mtDNA copy number and nuclear DNA (nuDNA) in 72,275 single cells derived from immortalized cell lines, patient-derived xenografts and primary human tumors. Cells typically contained thousands of mtDNA copies, but variation in mtDNA copy number was extensive and strongly associated with cell size. Pervasive whole-genome doubling events in nuDNA associated with stoichiometrically balanced adaptations in mtDNA copy number, implying that mtDNA-to-nuDNA ratio, rather than mtDNA copy number itself, mediated downstream phenotypes. Finally, multimodal analysis of DLP+ and single-cell RNA sequencing identified both somatic loss-of-function and germline noncoding variants in mtDNA linked to heteroplasmy-dependent changes in mtDNA copy number and mitochondrial transcription, revealing phenotypic adaptations to disrupted nuclear/mitochondrial balance.

DOI: https://doi.org/10.1038/s41588-024-01724-8
J Physiol. 2024 May 15.

Lack of compensatory mitophagy in skeletal muscles during sepsis.

Sami Sedraoui, Jean-Philippe Leduc-Gaudet, Dominique Mayaki, Alaa Moamer, Laurent Huck, Gilles Gouspillou, Basil J Petrof, Sabah Hussain.

  Skeletal muscle dysfunction is a major problem in critically ill patients suffering from sepsis. This condition is associated with mitochondrial dysfunction and increased autophagy in skeletal muscles. Autophagy is a proteolytic mechanism involved in eliminating dysfunctional cellular components, including mitochondria. The latter process, referred to as mitophagy, is essential for maintaining mitochondrial quality and skeletal muscle health. Recently, a fluorescent reporter system called mito-QC (i.e. mitochondrial quality control) was developed to specifically quantify mitophagy levels. In the present study, we used mito-QC transgenic mice and confocal microscopy to morphologically monitor mitophagy levels during sepsis. To induce sepsis, Mito-QC mice received Escherichia coli lipopolysaccharide (10 mg kg-1 i.p.) or phosphate-buffered saline and skeletal muscles (hindlimb and diaphragm) were excised 48 h later. In control groups, there was a negative correlation between the basal mitophagy level and overall muscle mitochondrial content. Sepsis increased general autophagy in both limb muscles and diaphragm but had no effect on mitophagy levels. Sepsis was associated with a downregulation of certain mitophagy receptors (Fundc1, Bcl2L13, Fkbp8 and Phbb2). The present study suggests that general autophagy and mitophagy can be dissociated from one another, and that the characteristic accumulation of damaged mitochondria in skeletal muscles under the condition of sepsis may reflect a failure of adequate compensatory mitophagy. KEY POINTS: There was a negative correlation between the basal level of skeletal muscle mitophagy and the mitochondrial content of individual muscles. Mitophagy levels in limb muscles and the diaphragm were unaffected by lipopolysaccharide (LPS)-induced sepsis. With the exception of BNIP3 in sepsis, LPS administration induced either no change or a downregulation of mitophagy receptors in skeletal muscles.

Keywords:  autophagy; mitochondria; mitophagy; mito‐QC; sepsis; skeletal muscles

DOI:  https://doi.org/10.1113/JP286216
Nat Rev Gastroenterol Hepatol. 2024 May 13.

Mitochondrial function and gastrointestinal diseases.

Parsa S Haque, Neeraj Kapur, Terrence A Barrett, Arianne L Theiss.

Mitochondria are dynamic organelles that function in cellular energy metabolism, intracellular and extracellular signalling, cellular fate and stress responses. Mitochondria of the intestinal epithelium, the cellular interface between self and enteric microbiota, have emerged as crucial in intestinal health. Mitochondrial dysfunction occurs in gastrointestinal diseases, including inflammatory bowel diseases and colorectal cancer. In this Review, we provide an overview of the current understanding of intestinal epithelial cell mitochondrial metabolism, function and signalling to affect tissue homeostasis, including gut microbiota composition. We also discuss mitochondrial-targeted therapeutics for inflammatory bowel diseases and colorectal cancer and the evolving concept of mitochondrial impairment as a consequence versus initiator of the disease.

DOI: https://doi.org/10.1038/s41575-024-00931-2
Int J Mol Sci. 2024 Apr 27. pii: 4783. [Epub ahead of print]25(9):

Mitochondria-Derived Vesicles, Sterile Inflammation, and Pyroptosis in Liver Cancer: Partners in Crime or Innocent Bystanders?

Flora Guerra, Francesca Romana Ponziani, Ferdinando Cardone, Cecilia Bucci, Emanuele Marzetti, Anna Picca.

  Alterations in cellular signaling, chronic inflammation, and tissue remodeling contribute to hepatocellular carcinoma (HCC) development. The release of damage-associated molecular patterns (DAMPs) upon tissue injury and the ensuing sterile inflammation have also been attributed a role in HCC pathogenesis. Cargoes of extracellular vesicles (EVs) and/or EVs themselves have been listed among circulating DAMPs but only partially investigated in HCC. Mitochondria-derived vesicles (MDVs), a subpopulation of EVs, are another missing link in the comprehension of the molecular mechanisms underlying the onset and progression of HCC biology. EVs have been involved in HCC growth, dissemination, angiogenesis, and immunosurveillance escape. The contribution of MDVs to these processes is presently unclear. Pyroptosis triggers systemic inflammation through caspase-dependent apoptotic cell death and is implicated in tumor immunity. The analysis of this process, together with MDV characterization, may help capture the relationship among HCC development, mitochondrial quality control, and inflammation. The combination of immune checkpoint inhibitors (i.e., atezolizumab and bevacizumab) has been approved as a synergistic first-line systemic treatment for unresectable or advanced HCC. The lack of biomarkers that may allow prediction of treatment response and, therefore, patient selection, is a major unmet need. Herein, we overview the molecular mechanisms linking mitochondrial dysfunction, inflammation, and pyroptosis, and discuss how immunotherapy targets, at least partly, these routes.

Keywords:  DAMPs; extracellular vesicles; gasdermin; hepatocellular carcinoma; immune checkpoints; immunotherapy; interleukin; miRNAs; mitochondrial-derived vesicles; mtDNA

DOI:  https://doi.org/10.3390/ijms25094783
J Transl Med. 2024 May 13. 22(1): 449

Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE.

Jixiang Du, Fuchen Liu, Xihan Liu, Dandan Zhao, Dongdong Wang, Hongsheng Sun, Chuanzhu Yan, Yuying Zhao.

  Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the impact of TP deficiency on lysosomes remains unclear, which are important for mitochondrial quality control and nucleic acid metabolism. Muscle biopsy tissue and skin fibroblasts from MNGIE patients, patients with m.3243 A > G mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and healthy controls (HC) were collected to perform mitochondrial and lysosomal functional analyses. In addition to mtDNA abnormalities, compared to controls distinctively reduced expression of LAMP1 and increased mitochondrial content were detected in the muscle tissue of MNGIE patients. Skin fibroblasts from MNGIE patients showed decreased expression of LAMP2, lowered lysosomal acidity, reduced enzyme activity and impaired protein degradation ability. TYMP knockout or TP inhibition in cells can also induce the similar lysosomal dysfunction. Using lysosome immunoprecipitation (Lyso- IP), increased mitochondrial proteins, decreased vesicular proteins and V-ATPase enzymes, and accumulation of various nucleosides were detected in lysosomes with TP deficiency. Treatment of cells with high concentrations of dThd and dUrd also triggers lysosomal dysfunction and disruption of mitochondrial homeostasis. Therefore, the results provided evidence that TP deficiency leads to nucleoside accumulation in lysosomes and lysosomal dysfunction, revealing the widespread disruption of organelles underlying MNGIE.

Keywords:  Lysosomal dysfunction; MNGIE; Nucleotide metabolism; TYMP; Thymidine phosphorylase

DOI:  https://doi.org/10.1186/s12967-024-05275-8
Nature. 2024 May 17.

Pig-organ transplants: what three human recipients have taught scientists.

Max Kozlov.



Keywords:  Cell biology; Medical research; Transcriptomics

DOI:  https://doi.org/10.1038/d41586-024-01453-2
Folia Neuropathol. 2024 ;pii: 52074. [Epub ahead of print]62(1): 21-31

A current view of mitochondria damage and the diversity of lipopigment inclusions in neuronal ceroid lipofuscinose type 2 from rectal biopsy.

Paulina Felczak, Aleksandra Kuźniar-Pałka, Agnieszka Ługowska, Elżbieta Stawicka, Sylwia Tarka, Hanna Mierzewska.

  Neuronal ceroid lipofuscinoses (NCLs) are a growing group of neurodegenerative storage diseases, in which specific features are sought to facilitate the creation of a universal diagnostic algorithm in the future. In our ultrastructural studies, the group of NCLs was represented by the CLN2 disease caused by a defect in the TPP1 gene encoding the enzyme tripeptidyl-peptidase 1. A 3.5-year-old girl was affected by this disease. Due to diagnostic difficulties, the spectrum of clinical, enzymatic, and genetic tests was extended to include analysis of the ultrastructure of cells from a rectal biopsy. The aim of our research was to search for pathognomonic features of CLN2 and to analyse the mitochondrial damage accompanying the disease. In the examined cells of the rectal mucosa, as expected, filamentous deposits of the curvilinear profile (CVP) type were found, which dominated quantitatively. Mixed deposits of the CVP/fingerprint profile (FPP) type were observed less frequently in the examined cells. A form of inclusions of unknown origin, not described so far in CLN2 disease, were wads of osmophilic material (WOMs). They occurred alone or co-formed mixed deposits. In addition, atypically damaged mitochondria were observed in muscularis mucosae. Their deformed cristae had contact with inclusions that looked like CVPs. Considering the confirmed role of the c subunit of the mitochondrial ATP synthase in the formation of filamentous lipopigment deposits in the group of NCLs, we suggest the possible significance of other mitochondrial proteins, such as mitochondrial contact site and cristae organizing system (MICOS), in the formation of these deposits. The presence of WOMs in the context of searching for ultrastructural pathognomonic features in CLN2 disease also requires further research.

Keywords:   CLN2 disease; curvilinear profiles; fingerprint profiles; mitochondria damage; rectal biopsy; neuronal ceroid lipofuscinoses

DOI:  https://doi.org/10.5114/fn.2023.133795
Apoptosis. 2024 May 17.

Mitophagy in health and disease. Molecular mechanisms, regulatory pathways, and therapeutic implications.

Mark S D'Arcy.

  Mitophagy, a specialised form of autophagy, selectively targeting damaged or dysfunctional mitochondria, and is crucial for maintaining cellular homeostasis and mitochondrial quality control. Dysregulation of mitophagy contributes to various pathological conditions, including cancer, neurodegenerative and cardiovascular diseases. This review presents a comprehensive analysis of the molecular mechanisms, regulatory pathways, and interplay with other cellular processes governing mitophagy, emphasizing its importance in physiological and pathological contexts. We explore the PINK1/Parkin-mediated and receptor-mediated mitophagy pathways, encompassing BNIP3/NIX, FUNDC1, and Bcl2-L-13. Additionally, we discuss post-translational modifications and cellular signalling pathways modulating mitophagy, as well as the connection between mitophagy and ageing, highlighting the decline in mitophagy efficiency and its impact on age-related pathologies. The review also investigates mitophagy's role in human diseases such as cancer, myocardial ischemia-reperfusion injury, Parkinson's, and Alzheimer's disease. We assess the potential of mitophagy-targeting therapeutic strategies, focusing on the development of dietary therapies, small molecules, drugs, and gene therapy approaches that modulate mitophagy levels and efficiency for treating these diseases and dysfunctions commonly observed in ageing individuals. In summary, this review offers an extensive overview of the molecular mechanisms and regulatory networks involved in mitophagy, its association with autophagy, and implications in human health and disease. By examining the potential of mitophagy-modulating therapies in disease and non-disease settings, we aim to inspire further research to develop innovative treatment strategies for various pathological conditions linked to mitochondrial dysfunction and to ageing.

Keywords:  Ageing; Autophagy; Mitophagy

DOI:  https://doi.org/10.1007/s10495-024-01977-y
J Neuroophthalmol. 2024 Jun 01. 44(2): e224-e226

Atypical Late-Onset Leber Hereditary Optic Neuropathy (LHON) Associated With T14484C Mutation.

Anas L Yasin, Carlos E Mendoza-Santiesteban, Mohamed M Khodeiry, Byron L Lam.

DOI: https://doi.org/10.1097/WNO.0000000000001835
Nat Med. 2024 May 14.

Dynamics of cognitive variability with age and its genetic underpinning in NIHR BioResource Genes and Cognition cohort participants.

Md Shafiqur Rahman, Emma Harrison, Heather Biggs, Chloe Seikus, Paul Elliott, Gerome Breen, Nathalie Kingston, John R Bradley, Steven M Hill, Brian D M Tom, Patrick F Chinnery.

A leading explanation for translational failure in neurodegenerative disease is that new drugs are evaluated late in the disease course when clinical features have become irreversible. Here, to address this gap, we cognitively profiled 21,051 people aged 17-85 years as part of the Genes and Cognition cohort within the National Institute for Health and Care Research BioResource across England. We describe the cohort, present cognitive trajectories and show the potential utility. Surprisingly, when studied at scale, the APOE genotype had negligible impact on cognitive performance. Different cognitive domains had distinct genetic architectures, with one indicating brain region-specific activation of microglia and another with glycogen metabolism. Thus, the molecular and cellular mechanisms underpinning cognition are distinct from dementia risk loci, presenting different targets to slow down age-related cognitive decline. Participants can now be recalled stratified by genotype and cognitive phenotype for natural history and interventional studies of neurodegenerative and other disorders.

DOI: https://doi.org/10.1038/s41591-024-02960-5
Nat Rev Endocrinol. 2024 May 17.

AMPK as a mediator of tissue preservation: time for a shift in dogma?

Henning Tim Langer, Maria Rohm, Marcus DaSilva Goncalves, Lykke Sylow.

Ground-breaking discoveries have established 5'-AMP-activated protein kinase (AMPK) as a central sensor of metabolic stress in cells and tissues. AMPK is activated through cellular starvation, exercise and drugs by either directly or indirectly affecting the intracellular AMP (or ADP) to ATP ratio. In turn, AMPK regulates multiple processes of cell metabolism, such as the maintenance of cellular ATP levels, via the regulation of fatty acid oxidation, glucose uptake, glycolysis, autophagy, mitochondrial biogenesis and degradation, and insulin sensitivity. Moreover, AMPK inhibits anabolic processes, such as lipogenesis and protein synthesis. These findings support the notion that AMPK is a crucial regulator of cell catabolism. However, studies have revealed that AMPK's role in cell homeostasis might not be as unidirectional as originally thought. This Review explores emerging evidence for AMPK as a promoter of cell survival and an enhancer of anabolic capacity in skeletal muscle and adipose tissue during catabolic crises. We discuss AMPK-activating interventions for tissue preservation during tissue wasting in cancer-associated cachexia and explore the clinical potential of AMPK activation in wasting conditions. Overall, we provide arguments that call for a shift in the current dogma of AMPK as a mere regulator of cell catabolism, concluding that AMPK has an unexpected role in tissue preservation.

DOI: https://doi.org/10.1038/s41574-024-00992-y
J Neurol Sci. 2024 May 14. pii: S0022-510X(24)00188-6. [Epub ahead of print]461 123053

Characterization of clinical serum cardiac biomarker levels in individuals with Friedreich ataxia.

David R Lynch, Sonal Sharma, Patrick Hearle, Nathaniel Greeley, Katherine Gunther, Medina Keita, Cassandra Strawser, Lauren Hauser, Courtney Park, Kimberly Schadt, Kimberly Y Lin.

  Friedreich ataxia is a progressive autosomal recessive neurodegenerative disorder characterized by ataxia, dyscoordination, and cardiomyopathy. A subset of patients with Friedreich ataxia have elevated levels of serum cardiac troponin I, but associations with disease outcomes and features of cardiomyopathy remain unclear. In this study, we characterized clinically obtained serum cardiac biomarker levels including troponin I, troponin T, and B-type natriuretic peptide in subjects with Friedreich ataxia and evaluated their association with markers of disease. While unprovoked troponin I levels were elevated in 36% of the cohort, cTnI levels associated with a cardiac event (provoked) were higher than unprovoked levels. In multivariate linear regression models, younger age predicted increased troponin I values, and in logistic regression models younger age, female sex, and marginally longer GAA repeat length predicted abnormal troponin I levels. In subjects with multiple assessments, mean unprovoked troponin I levels decreased slightly over time. The presence of abnormal troponin I values and their levels were predicted by echocardiographic measures of hypertrophy. In addition, troponin I levels predicted long-term markers of clinical cardiac dysfunction over time to a modest degree. Consequently, troponin I values provide a marker of hypertrophy but only a minimally predictive biomarker for later cardiac manifestations of disease such as systolic dysfunction or arrhythmia.

Keywords:  Cardiomyopathy; Hypertrophy; Mitochondria

DOI:  https://doi.org/10.1016/j.jns.2024.123053
Cell. 2024 May 09. pii: S0092-8674(24)00455-0. [Epub ahead of print]

The first two blastomeres contribute unequally to the human embryo.

Sergi Junyent, Maciej Meglicki, Roman Vetter, Rachel Mandelbaum, Catherine King, Ekta M Patel, Lisa Iwamoto-Stohl, Clare Reynell, Dong-Yuan Chen, Patrizia Rubino, Nabil Arrach, Richard J Paulson, Dagmar Iber, Magdalena Zernicka-Goetz.

  Retrospective lineage reconstruction of humans predicts that dramatic clonal imbalances in the body can be traced to the 2-cell stage embryo. However, whether and how such clonal asymmetries arise in the embryo is unclear. Here, we performed prospective lineage tracing of human embryos using live imaging, non-invasive cell labeling, and computational predictions to determine the contribution of each 2-cell stage blastomere to the epiblast (body), hypoblast (yolk sac), and trophectoderm (placenta). We show that the majority of epiblast cells originate from only one blastomere of the 2-cell stage embryo. We observe that only one to three cells become internalized at the 8-to-16-cell stage transition. Moreover, these internalized cells are more frequently derived from the first cell to divide at the 2-cell stage. We propose that cell division dynamics and a cell internalization bottleneck in the early embryo establish asymmetry in the clonal composition of the future human body.

Keywords:  2-cell blastomere asymmetries; epiblast; human development; human embryo; hypoblast; lineage tracing; non-invasive live imaging; placenta; preimplantation development

DOI:  https://doi.org/10.1016/j.cell.2024.04.029
Neurol Clin Pract. 2024 Jun;14(3): e200303

Friedreich Ataxia Caregiver-Reported Health Index: Development of a Novel, Disease-Specific Caregiver-Reported Outcome Measure.

Jamison Seabury, Anika Varma, Jennifer Weinstein, Spencer J Rosero, Charlotte Engebrecht, Shaweta Khosa, Christine Zizzi, Ellen S Wagner, Danae Alexandrou, Brittany L Cohen, Nuran Dilek, John M Heatwole, David R Lynch, Courtney C Park, McKenzie Wells, S H Subramony, Chad R Heatwole.

Background and Objectives: The Friedreich ataxia (FRDA) scientific community needs access to patient-centered outcome measures that satisfy regulatory guidelines and are capable of tracking clinically meaningful changes in FRDA disease burden. The objective of this research was to develop a novel, disease-specific caregiver-reported outcome measure for use in FRDA research and clinical care.Methods: In prior work, we conducted qualitative interviews and a cross-sectional study of FRDA caregivers and patients to determine the symptoms of greatest importance to individuals with FRDA. We designed the Friedreich Ataxia Caregiver-Reported Health Index (FACR-HI) to serially measure the symptoms of greatest importance to patients and utilized factor analysis, beta testing, reliability testing, and cross-sectional subgroup analysis to further evaluate and optimize this disease-specific outcome measure.
Results: The FACR-HI was designed to measure total disease burden and disease burden in 18 symptomatic domains. The FACR-HI total score demonstrated high internal consistency (Cronbach's α = 0.98) and test-retest reliability (intraclass correlation coefficient = 0.96). Beta interview participants found the FACR-HI to be highly relevant, comprehensive, and easy to use. FACR-HI total and subscale scores were associated with functional staging for ataxia scores and speech impairment.
Discussion: Initial evaluation of the FACR-HI supports its content validity, test-retest reliability, and construct validity as a caregiver-reported outcome measure for assessing how pediatric individuals with FRDA feel and function. The FACR-HI provides a potential mechanism to quantify changes in multifactorial FRDA disease burden during future clinical trials.

DOI: https://doi.org/10.1212/CPJ.0000000000200300