bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023–06–18
23 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. How does mitochondrial import machinery fine-tune mitophagy? Different paths and one destination.
  2. Neurological Phenotypes in Mouse Models of Mitochondrial Disease and Relevance to Human Neuropathology.
  3. Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria.
  4. Kearns-Sayre syndrome: Two case reports and a review for the primary care physician.
  5. Role of Mutations of Mitochondrial Aminoacyl-tRNA Synthetases Genes on Epileptogenesis.
  6. A mitochondrial iron-responsive pathway regulated by DELE1.
  7. The disease-causing mutation p.F907I reveals a novel pathogenic mechanism for POLγ-related diseases.
  8. Systematic Approaches to Study Eclipsed Targeting of Proteins Uncover a New Family of Mitochondrial Proteins.
  9. Mitochondrial Transfer to Host Cells from Ex Vivo Expanded Donor Hematopoietic Stem Cells.
  10. Mitochondrial control of innate immune responses.
  11. Most advanced synthetic human embryos yet spark controversy.
  12. In search for mitochondrial biomarkers of Parkinson's disease: Findings in parkin-mutant human fibroblasts.
  13. A worm's life: AMPK links muscle mitochondrial dynamics to physical fitness and healthy aging in Caenorhabditis elegans.
  14. Identification of m.3243A>G mitochondrial DNA mutation in patients with cerebellar ataxia.
  15. PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid.
  16. The mitochondrial calcium uniporter (MCU) activates mitochondrial respiration and enhances mobility by regulating mitochondrial redox state.
  17. Mitochondrial DNA quantification correlates with the developmental potential of human euploid blastocysts but not with that of mosaic blastocysts.
  18. Optimized testing strategy for the diagnosis of GAA-FGF14 ataxia/spinocerebellar ataxia 27B.
  19. Taurine supplement makes animals live longer - what it means for people is unclear.
  20. Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.
  21. Mitochondrial remodeling and energy metabolism adaptations in colonic crypts during spontaneous epithelial repair after colitis induction in mice.
  22. First herpesvirus gene therapy.
  23. PHAF1/MYTHO is a novel autophagy regulator that controls muscle integrity.
  1. Trends Endocrinol Metab. 2023 Jun 13. pii: S1043-2760(23)00107-8. [Epub ahead of print]
    How does mitochondrial import machinery fine-tune mitophagy? Different paths and one destination.
    Mohamed A Eldeeb, Andrea Soumbasis, Edward A Fon.
      Given their polyvalent roles, an intrinsic challenge that mitochondria face is the continuous exposure to various stressors including mitochondrial import defects, which leads to their dysfunction. Recent work has unveiled a presequence translocase-associated import motor (PAM) complex-dependent quality control pathway whereby misfolded proteins mitigate mitochondrial protein import and subsequently elicit mitophagy without the loss of mitochondrial membrane potential.
    Keywords:  PINK1; TOM complex; mitochondrial import; mitochondrial quality control; mitophagy; protein quality control
    DOI:  https://doi.org/10.1016/j.tem.2023.05.005
  2. Int J Mol Sci. 2023 Jun 02. pii: 9698. [Epub ahead of print]24(11):
    Neurological Phenotypes in Mouse Models of Mitochondrial Disease and Relevance to Human Neuropathology.
    Elizaveta A Olkhova, Laura A Smith, Carla Bradshaw, Gráinne S Gorman, Daniel Erskine, Yi Shiau Ng.
      Mitochondrial diseases represent the most common inherited neurometabolic disorders, for which no effective therapy currently exists for most patients. The unmet clinical need requires a more comprehensive understanding of the disease mechanisms and the development of reliable and robust in vivo models that accurately recapitulate human disease. This review aims to summarise and discuss various mouse models harbouring transgenic impairments in genes that regulate mitochondrial function, specifically their neurological phenotype and neuropathological features. Ataxia secondary to cerebellar impairment is one of the most prevalent neurological features of mouse models of mitochondrial dysfunction, consistent with the observation that progressive cerebellar ataxia is a common neurological manifestation in patients with mitochondrial disease. The loss of Purkinje neurons is a shared neuropathological finding in human post-mortem tissues and numerous mouse models. However, none of the existing mouse models recapitulate other devastating neurological phenotypes, such as refractory focal seizures and stroke-like episodes seen in patients. Additionally, we discuss the roles of reactive astrogliosis and microglial reactivity, which may be driving the neuropathology in some of the mouse models of mitochondrial dysfunction, as well as mechanisms through which cellular death may occur, beyond apoptosis, in neurons undergoing mitochondrial bioenergy crisis.
    Keywords:  cerebellar ataxia; inhibitory neurons; neurodegeneration
    DOI:  https://doi.org/10.3390/ijms24119698
  3. Life Sci Alliance. 2023 Sep;pii: e202302127. [Epub ahead of print]6(9):
    Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria.
    Jun Yong Kim, Ilian Atanassov, Frederik Dethloff, Lara Kroczek, Thomas Langer.
      Mitochondrial dysfunction and cellular senescence are hallmarks of aging. However, the relationship between these two phenomena remains incompletely understood. In this study, we investigated the rewiring of mitochondria upon development of the senescent state in human IMR90 fibroblasts. Determining the bioenergetic activities and abundance of mitochondria, we demonstrate that senescent cells accumulate mitochondria with reduced OXPHOS activity, resulting in an overall increase of mitochondrial activities in senescent cells. Time-resolved proteomic analyses revealed extensive reprogramming of the mitochondrial proteome upon senescence development and allowed the identification of metabolic pathways that are rewired with different kinetics upon establishment of the senescent state. Among the early responding pathways, the degradation of branched-chain amino acid was increased, whereas the one carbon folate metabolism was decreased. Late-responding pathways include lipid metabolism and mitochondrial translation. These signatures were confirmed by metabolic flux analyses, highlighting metabolic rewiring as a central feature of mitochondria in cellular senescence. Together, our data provide a comprehensive view on the changes in mitochondrial proteome in senescent cells and reveal how the mitochondrial metabolism is rewired in senescent cells.
    DOI:  https://doi.org/10.26508/lsa.202302127
  4. J Family Med Prim Care. 2023 Apr;12(4): 792-795
    Kearns-Sayre syndrome: Two case reports and a review for the primary care physician.
    Chad Richmond, Leonard Powell, Zachary D Brittingham, Alison Mancuso.
      Kearns-Sayre syndrome (KSS) is a mitochondrial encephalopathic disorder. Because mitochondria are ubiquitous organelles that are present in almost every human tissue, their dysfunction can affect nearly any organ system and give rise to a wide range of clinical characteristics. 1: As is the case with most diseases associated with mitochondrial DNA (mtDNA) mutations, the clinical features of KSS were defined before modern molecular genetic classifications emerged. 2: The exact prevalence of KSS is unknown; however, estimates place it at about 1:100,000 people. Although it is a rather rare syndrome, the ability to recognize or consider KSS as part of a differential diagnosis is crucial. Reported here are two case reports: 1) a 30-year-old Caucasian female patient who presented for evaluation to her primary care physician's office and, and 2) A 57-year-old Caucasian female patient long-term C care resident. Guidelines are listed for management as a primary care physician as well as signs and symptoms that are often associated with Kearns-Sayre syndrome and other mitochondrial disorders.
    Keywords:  Encephalopathy; Kearns–Sayre syndrome; mitochondrial DNA; mitochondrial disease
    DOI:  https://doi.org/10.4103/jfmpc.jfmpc_1790_22
  5. Mol Neurobiol. 2023 Jun 14.
    Role of Mutations of Mitochondrial Aminoacyl-tRNA Synthetases Genes on Epileptogenesis.
    Ling-Yue Kong, Yi-Ze Wu, Run-Qi Cheng, Pei-Han Wang, Bi-Wen Peng.
      Mitochondria are the structures in cells that are responsible for producing energy. They contain a specific translation unit for synthesizing mitochondria-encoded respiratory chain components: the mitochondrial DNA (mt DNA). Recently, a growing number of syndromes associated with the dysfunction of mt DNA translation have been reported. However, the functions of these diseases still need to be precise and thus attract much attention. Mitochondrial tRNAs (mt tRNAs) are encoded by mt DNA; they are the primary cause of mitochondrial dysfunction and are associated with a wide range of pathologies. Previous research has shown the role of mt tRNAs in the epileptic mechanism. This review will focus on the function of mt tRNA and the role of mitochondrial aminoacyl-tRNA synthetase (mt aaRS) in order to summarize some common relevant mutant genes of mt aaRS that cause epilepsy and the specific symptoms of the disease they cause.
    Keywords:  Aminoacyl-tRNA synthetase; Epilepsy; Mitochondrial disorders; Mitochondrial tRNA
    DOI:  https://doi.org/10.1007/s12035-023-03429-1
  6. Mol Cell. 2023 Jun 15. pii: S1097-2765(23)00413-6. [Epub ahead of print]83(12): 2059-2076.e6
    A mitochondrial iron-responsive pathway regulated by DELE1.
    Yusuke Sekine, Ryan Houston, Eva-Maria Eckl, Evelyn Fessler, Derek P Narendra, Lucas T Jae, Shiori Sekine.
      The heme-regulated kinase HRI is activated under heme/iron deficient conditions; however, the underlying molecular mechanism is incompletely understood. Here, we show that iron-deficiency-induced HRI activation requires the mitochondrial protein DELE1. Notably, mitochondrial import of DELE1 and its subsequent protein stability are regulated by iron availability. Under steady-state conditions, DELE1 is degraded by the mitochondrial matrix-resident protease LONP1 soon after mitochondrial import. Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). Ablation of this DELE1-HRI-ISR pathway in an erythroid cell model enhances cell death under iron-limited conditions, suggesting a cell-protective role for this pathway in iron-demanding cell lineages. Our findings highlight mitochondrial import regulation of DELE1 as the core component of a previously unrecognized mitochondrial iron responsive pathway that elicits stress signaling following perturbation of iron homeostasis.
    Keywords:  DELE1; HRI; LONP1; erythroid cells; integrated stress response; iron; mitochondria; mitochondrial import; mitochondrial proteostasis
    DOI:  https://doi.org/10.1016/j.molcel.2023.05.031
  7. Biochim Biophys Acta Mol Basis Dis. 2023 Jun 09. pii: S0925-4439(23)00152-7. [Epub ahead of print] 166786
    The disease-causing mutation p.F907I reveals a novel pathogenic mechanism for POLγ-related diseases.
    Direnis Erdinc, Bertil Macao, Sebastian Valenzuela, Nicole Lesko, Karin Naess, Bradley Peter, Helene Bruhn, Anna Wedell, Anna Wredenberg, Maria Falkenberg.
      Mutations in the catalytic domain of mitochondrial DNA polymerase γ (POLγ) cause a broad spectrum of clinical conditions. POLγ mutations impair mitochondrial DNA replication, thereby causing deletions and/or depletion of mitochondrial DNA, which in turn impair biogenesis of the oxidative phosphorylation system. We here identify a patient with a homozygous p.F907I mutation in POLγ, manifesting a severe clinical phenotype with developmental arrest and rapid loss of skills from 18 months of age. Magnetic resonance imaging of the brain revealed extensive white matter abnormalities, Southern blot of muscle mtDNA demonstrated depletion of mtDNA and the patient deceased at 23 months of age. Interestingly, the p.F907I mutation does not affect POLγ activity on single-stranded DNA or its proofreading activity. Instead, the mutation affects unwinding of parental double-stranded DNA at the replication fork, impairing the ability of the POLγ to support leading-strand DNA synthesis with the TWINKLE helicase. Our results thus reveal a novel pathogenic mechanism for POLγ-related diseases.
    Keywords:  DNA polymerase γ; Disease; Mitochondrial replication; TWINKLE helicase; mtDNA
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166786
  8. Cells. 2023 Jun 05. pii: 1550. [Epub ahead of print]12(11):
    Systematic Approaches to Study Eclipsed Targeting of Proteins Uncover a New Family of Mitochondrial Proteins.
    Maayan Mark, Ofir Klein, Yu Zhang, Koyeli Das, Adi Elbaz, Reut Noa Hazan, Michal Lichtenstein, Norbert Lehming, Maya Schuldiner, Ophry Pines.
      Dual localization or dual targeting refers to the phenomenon by which identical, or almost identical, proteins are localized to two (or more) separate compartments of the cell. From previous work in the field, we had estimated that a third of the mitochondrial proteome is dual-targeted to extra-mitochondrial locations and suggested that this abundant dual targeting presents an evolutionary advantage. Here, we set out to study how many additional proteins whose main activity is outside mitochondria are also localized, albeit at low levels, to mitochondria (eclipsed). To do this, we employed two complementary approaches utilizing the α-complementation assay in yeast to uncover the extent of such an eclipsed distribution: one systematic and unbiased and the other based on mitochondrial targeting signal (MTS) predictions. Using these approaches, we suggest 280 new eclipsed distributed protein candidates. Interestingly, these proteins are enriched for distinctive properties compared to their exclusively mitochondrial-targeted counterparts. We focus on one unexpected eclipsed protein family of the Triose-phosphate DeHydrogenases (TDH) and prove that, indeed, their eclipsed distribution in mitochondria is important for mitochondrial activity. Our work provides a paradigm of deliberate eclipsed mitochondrial localization, targeting and function, and should expand our understanding of mitochondrial function in health and disease.
    Keywords:  TDH2; TDH3; dual protein targeting; eclipsed protein targeting; mitochondria; yeast model system
    DOI:  https://doi.org/10.3390/cells12111550
  9. Cells. 2023 May 25. pii: 1473. [Epub ahead of print]12(11):
    Mitochondrial Transfer to Host Cells from Ex Vivo Expanded Donor Hematopoietic Stem Cells.
    Hiroki Kawano, Yuko Kawano, Chen Yu, Mark W LaMere, Matthew J McArthur, Michael W Becker, Scott W Ballinger, Satoshi Gojo, Roman A Eliseev, Laura M Calvi.
      Mitochondrial dysfunction is observed in various conditions, from metabolic syndromes to mitochondrial diseases. Moreover, mitochondrial DNA (mtDNA) transfer is an emerging mechanism that enables the restoration of mitochondrial function in damaged cells. Hence, developing a technology that facilitates the transfer of mtDNA can be a promising strategy for the treatment of these conditions. Here, we utilized an ex vivo culture of mouse hematopoietic stem cells (HSCs) and succeeded in expanding the HSCs efficiently. Upon transplantation, sufficient donor HSC engraftment was attained in-host. To assess the mitochondrial transfer via donor HSCs, we used mitochondrial-nuclear exchange (MNX) mice with nuclei from C57BL/6J and mitochondria from the C3H/HeN strain. Cells from MNX mice have C57BL/6J immunophenotype and C3H/HeN mtDNA, which is known to confer a higher stress resistance to mitochondria. Ex vivo expanded MNX HSCs were transplanted into irradiated C57BL/6J mice and the analyses were performed at six weeks post transplantation. We observed high engraftment of the donor cells in the bone marrow. We also found that HSCs from the MNX mice could transfer mtDNA to the host cells. This work highlights the utility of ex vivo expanded HSC to achieve the mitochondrial transfer from donor to host in the transplant setting.
    Keywords:  MNX mouse, 5; ex vivo HSC expansion 3; in vivo mitochondrial transfer; mitochondrial DNA 2
    DOI:  https://doi.org/10.3390/cells12111473
  10. Front Immunol. 2023 ;14 1166214
    Mitochondrial control of innate immune responses.
    Shasha Chen, Zhiyong Liao, Pinglong Xu.
      Mitochondria are versatile organelles and essential components of numerous biological processes such as energy metabolism, signal transduction, and cell fate determination. In recent years, their critical roles in innate immunity have come to the forefront, highlighting impacts on pathogenic defense, tissue homeostasis, and degenerative diseases. This review offers an in-depth and comprehensive examination of the multifaceted mechanisms underlying the interactions between mitochondria and innate immune responses. We will delve into the roles of healthy mitochondria as platforms for signalosome assembly, the release of mitochondrial components as signaling messengers, and the regulation of signaling via mitophagy, particularly to cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling and inflammasomes. Furthermore, the review will explore the impacts of mitochondrial proteins and metabolites on modulating innate immune responses, the polarization of innate immune cells, and their implications on infectious and inflammatory diseases.
    Keywords:  MAVS; cGAS-STING; inflammasome; innate immunity; mitochondria; mitochondrial metabolism; mitophagy; mtDNA
    DOI:  https://doi.org/10.3389/fimmu.2023.1166214
  11. Nature. 2023 Jun 16.
    Most advanced synthetic human embryos yet spark controversy.
    Philip Ball.
      
    Keywords:  Cell biology; Developmental biology
    DOI:  https://doi.org/10.1038/d41586-023-01992-0
  12. Biochim Biophys Acta Mol Basis Dis. 2023 Jun 10. pii: S0925-4439(23)00153-9. [Epub ahead of print]1869(7): 166787
    In search for mitochondrial biomarkers of Parkinson's disease: Findings in parkin-mutant human fibroblasts.
    Iryna Kamienieva, Agata Charzyńska, Jerzy Duszyński, Dominika Malińska, Joanna Szczepanowska.
      Most cases of Parkinson's disease (PD) are idiopathic, with unknown aetiology and genetic background. However, approximately 10 % of cases are caused by defined genetic mutations, among which mutations in the parkin gene are the most common. There is increasing evidence of the involvement of mitochondrial dysfunction in the development of both idiopathic and genetic PD. However, the data on mitochondrial changes reported by different studies are inconsistent, which can reflect the variability in genetic background of the disease. Mitochondria, as a plastic and dynamic organelles, are the first place in the cell to respond to external and internal stress. In this work, we characterized mitochondrial function and dynamics (network morphology and turnover regulation) in primary fibroblasts from PD patients with parkin mutations. We performed clustering analysis of the obtained data to compare the profiles of mitochondrial parameters in PD patients and healthy donors. This allowed to extract the features characteristic for PD patients fibroblasts, which were a smaller and less complex mitochondrial network and decreased levels of mitochondrial biogenesis regulators and mitophagy mediators. The approach we used allowed a comprehensive characteristics of elements common for mitochondrial dynamics remodelling accompanying pathogenic mutation. This may be helpful in the deciphering key pathomechanisms of the PD disease.
    Keywords:  Mitochondria; Parkin; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166787
  13. J Cardiovasc Aging. 2023 ;pii: 25. [Epub ahead of print]3(3):
    A worm's life: AMPK links muscle mitochondrial dynamics to physical fitness and healthy aging in Caenorhabditis elegans.
    Vihang A Narkar.
      
    Keywords:  AMPK; Exercise; mitochondrial dynamics
    DOI:  https://doi.org/10.20517/jca.2023.14
  14. J Formos Med Assoc. 2023 Jun 11. pii: S0929-6646(23)00200-0. [Epub ahead of print]
    Identification of m.3243A>G mitochondrial DNA mutation in patients with cerebellar ataxia.
    Nai-Yi Liao, Kuan-Lin Lai, Yi-Chu Liao, Cheng-Tsung Hsiao, Yi-Chung Lee.
       BACKGROUND: The mitochondrial DNA m.3243A>G mutation can affect mitochondrial function and lead to a wide phenotypic spectrum, including mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, diabetes mellitus, hearing impairment, cardiac involvement, epilepsy, migraine, myopathy, and cerebellar ataxia. However, m.3243A>G has been rarely reported in patients with cerebellar ataxia as their predominant manifestation. The aim of this study is to investigate the prevalence and clinical features of m.3243A>G in a Taiwanese cohort of cerebellar ataxia with unknown genetic diagnosis.
    METHODS: This retrospective cohort study conducted the mutation analysis of m.3243A>G by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) in 232 unrelated Han Chinese patients with genetically-undetermined cerebellar ataxia. The clinical presentation and neuroimaging features of patients with m.3243A>G mutation-related cerebellar ataxia were characterized.
    RESULTS: We identified two patients harboring m.3243A>G mutation. These patients have suffered from apparently sporadic and slowly progressive cerebellar ataxia since age 52 and 35 years, respectively. Both patients had diabetes mellitus and/or hearing impairment. The neuroimaging studies revealed generalized brain atrophy with predominantly cerebellar involvement in both individuals and bilateral basal ganglia calcifications in one of the patients.
    CONCLUSION: Mitochondrial m.3243A>G mutation accounted for 0.9% (2/232) of genetically-undetermined cerebellar ataxia in the Han Chinese cohort in Taiwan. These findings highlight the importance of investigating m.3243A>G in patients with genetically-undetermined cerebellar ataxia.
    Keywords:  Cerebellar ataxia; MELAS; m.3243A>G
    DOI:  https://doi.org/10.1016/j.jfma.2023.05.031
  15. EMBO J. 2023 Jun 12. e113908
    PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid.
    Valerie Perea, Christian Cole, Justine Lebeau, Vivian Dolina, Kelsey R Baron, Aparajita Madhavan, Jeffery W Kelly, Danielle A Grotjahn, R Luke Wiseman.
      Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are linked in the onset and pathogenesis of numerous diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria during ER stress. The PERK signaling arm of the unfolded protein response (UPR) has emerged as a prominent ER stress-responsive signaling pathway that regulates diverse aspects of mitochondrial biology. Here, we show that PERK activity promotes adaptive remodeling of mitochondrial membrane phosphatidic acid (PA) to induce protective mitochondrial elongation during acute ER stress. We find that PERK activity is required for ER stress-dependent increases in both cellular PA and YME1L-dependent degradation of the intramitochondrial PA transporter PRELID1. These two processes lead to the accumulation of PA on the outer mitochondrial membrane where it can induce mitochondrial elongation by inhibiting mitochondrial fission. Our results establish a new role for PERK in the adaptive remodeling of mitochondrial phospholipids and demonstrate that PERK-dependent PA regulation adapts organellar shape in response to ER stress.
    Keywords:  endoplasmic reticulum (ER) stress; mitochondrial morphology; phosphatidic acid; unfolded protein response (UPR)
    DOI:  https://doi.org/10.15252/embj.2023113908
  16. Redox Biol. 2023 Jun 04. pii: S2213-2317(23)00160-X. [Epub ahead of print]64 102759
    The mitochondrial calcium uniporter (MCU) activates mitochondrial respiration and enhances mobility by regulating mitochondrial redox state.
    Anna Weiser, Aurélie Hermant, Flavien Bermont, Federico Sizzano, Sonia Karaz, Pilar Alvarez-Illera, Jaime Santo-Domingo, Vincenzo Sorrentino, Jerome N Feige, Umberto De Marchi.
      Regulation of mitochondrial redox balance is emerging as a key event for cell signaling in both physiological and pathological conditions. However, the link between the mitochondrial redox state and the modulation of these conditions remains poorly defined. Here, we discovered that activation of the evolutionary conserved mitochondrial calcium uniporter (MCU) modulates mitochondrial redox state. By using mitochondria-targeted redox and calcium sensors and genetic MCU-ablated models, we provide evidence of the causality between MCU activation and net reduction of mitochondrial (but not cytosolic) redox state. Redox modulation of redox-sensitive groups via MCU stimulation is required for maintaining respiratory capacity in primary human myotubes and C. elegans, and boosts mobility in worms. The same benefits are obtained bypassing MCU via direct pharmacological reduction of mitochondrial proteins. Collectively, our results demonstrate that MCU regulates mitochondria redox balance and that this process is required to promote the MCU-dependent effects on mitochondrial respiration and mobility.
    Keywords:  C. elegans; Calcium signaling; MCU; Mitochondria; Redox biology; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.redox.2023.102759
  17. BMC Pregnancy Childbirth. 2023 Jun 15. 23(1): 447
    Mitochondrial DNA quantification correlates with the developmental potential of human euploid blastocysts but not with that of mosaic blastocysts.
    Wen Luo, Yi-Min Zheng, Yan Hao, Ying Zhang, Ping Zhou, Zhaolian Wei, Yunxia Cao, Dawei Chen.
       PURPOSE: We aimed to study the association between adjusted mtDNA levels in human trophectoderm biopsy samples and the developmental potential of euploid and mosaic blastocysts.
    METHODS: We analyzed relative mtDNA levels in 2,814 blastocysts obtained from 576 couples undergoing preimplantation genetic testing for aneuploidy from June 2018 to June 2021. All patients underwent in vitro fertilization in a single clinic; the study was blinded-mtDNA content was unknown at the time of single embryo transfer. The fate of the euploid or mosaic embryos transferred was compared with mtDNA levels.
    RESULTS: Euploid embryos had lower mtDNA than aneuploid and mosaic embryos. Embryos biopsied on Day 5 had higher mtDNA than those biopsied on Day 6. No difference was detected in mtDNA scores between embryos derived from oocytes of different maternal ages. Linear mixed model suggested that blastulation rate was associated with mtDNA score. Moreover, the specific next-generation sequencing platform used have a significant effect on the observed mtDNA content. Euploid embryos with higher mtDNA content presented significantly higher miscarriage rates and lower live birth rates, while no significant difference was observed in the mosaic cohort.
    CONCLUSION: Our results will aid in improving methods for analyzing the association between mtDNA level and blastocyst viability.
    Keywords:  Blastocyst; Embryo viability; Mitochondrial genome; Mitochondrion; Preimplantation genetic testing; mtDNA quantification
    DOI:  https://doi.org/10.1186/s12884-023-05760-w
  18. Sci Rep. 2023 Jun 15. 13(1): 9737
    Optimized testing strategy for the diagnosis of GAA-FGF14 ataxia/spinocerebellar ataxia 27B.
    Céline Bonnet, David Pellerin, Virginie Roth, Guillemette Clément, Marion Wandzel, Laëtitia Lambert, Solène Frismand, Marian Douarinou, Anais Grosset, Ines Bekkour, Frédéric Weber, Florent Girardier, Clément Robin, Stéphanie Cacciatore, Myriam Bronner, Carine Pourié, Natacha Dreumont, Salomé Puisieux, Pablo Iruzubieta, Marie-Josée Dicaire, François Evoy, Marie-France Rioux, Armand Hocquel, Roberta La Piana, Matthis Synofzik, Henry Houlden, Matt C Danzi, Stephan Zuchner, Bernard Brais, Mathilde Renaud.
      Dominantly inherited GAA repeat expansions in FGF14 are a common cause of spinocerebellar ataxia (GAA-FGF14 ataxia; spinocerebellar ataxia 27B). Molecular confirmation of FGF14 GAA repeat expansions has thus far mostly relied on long-read sequencing, a technology that is not yet widely available in clinical laboratories. We developed and validated a strategy to detect FGF14 GAA repeat expansions using long-range PCR, bidirectional repeat-primed PCRs, and Sanger sequencing. We compared this strategy to targeted nanopore sequencing in a cohort of 22 French Canadian patients and next validated it in a cohort of 53 French index patients with unsolved ataxia. Method comparison showed that capillary electrophoresis of long-range PCR amplification products significantly underestimated expansion sizes compared to nanopore sequencing (slope, 0.87 [95% CI, 0.81 to 0.93]; intercept, 14.58 [95% CI, - 2.48 to 31.12]) and gel electrophoresis (slope, 0.84 [95% CI, 0.78 to 0.97]; intercept, 21.34 [95% CI, - 27.66 to 40.22]). The latter techniques yielded similar size estimates. Following calibration with internal controls, expansion size estimates were similar between capillary electrophoresis and nanopore sequencing (slope: 0.98 [95% CI, 0.92 to 1.04]; intercept: 10.62 [95% CI, - 7.49 to 27.71]), and gel electrophoresis (slope: 0.94 [95% CI, 0.88 to 1.09]; intercept: 18.81 [95% CI, - 41.93 to 39.15]). Diagnosis was accurately confirmed for all 22 French Canadian patients using this strategy. We also identified 9 French patients (9/53; 17%) and 2 of their relatives who carried an FGF14 (GAA)≥250 expansion. This novel strategy reliably detected and sized FGF14 GAA expansions, and compared favorably to long-read sequencing.
    DOI:  https://doi.org/10.1038/s41598-023-36654-8
  19. Nature. 2023 Jun 09.
    Taurine supplement makes animals live longer - what it means for people is unclear.
    Myriam Vidal Valero.
      
    Keywords:  Ageing; Metabolism; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-023-01910-4
  20. Am J Hum Genet. 2023 Jun 06. pii: S0002-9297(23)00166-0. [Epub ahead of print]
    Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.
    Paulina Cunha, Emilien Petit, Marie Coutelier, Giulia Coarelli, Caterina Mariotti, Jennifer Faber, Judith Van Gaalen, Joana Damasio, Zofia Fleszar, Michele Tosi, Clarissa Rocca, Giovanna De Michele, Martina Minnerop, Claire Ewenczyk, Filippo M Santorelli, Anna Heinzmann, Thomas Bird, Matthias Amprosi, Elisabetta Indelicato, Alberto Benussi, Perrine Charles, Claudia Stendel, Silvia Romano, Marina Scarlato, Isabelle Le Ber, Maria Teresa Bassi, Mercedes Serrano, Tanja Schmitz-Hübsch, Sarah Doss, Gijs A J Van Velzen, Quentin Thomas, Antonio Trabacca, Juan Dario Ortigoza-Escobar, Stefano D'Arrigo, Dagmar Timmann, Chiara Pantaleoni, Andrea Martinuzzi, Elsa Besse-Pinot, Luca Marsili, Ettore Cioffi, Francesco Nicita, Alejandro Giorgetti, Isabella Moroni, Romina Romaniello, Carlo Casali, Penina Ponger, Giorgio Casari, Susanne T De Bot, Giovanni Ristori, Lubov Blumkin, Barbara Borroni, Cyril Goizet, Cecilia Marelli, Sylvia Boesch, Mathieu Anheim, Alessandro Filla, Henry Houlden, Enrico Bertini, Thomas Klopstock, Matthis Synofzik, Florence Riant, Ginevra Zanni, Stefania Magri, Daniela Di Bella, Lorenzo Nanetti, Jorge Sequeiros, Jorge Oliveira, Bart Van de Warrenburg, Ludger Schöls, Franco Taroni, Alexis Brice, Alexandra Durr.
      Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucleotide variants or deletions in one of seven genes: CACNA1A (239 subjects), PRKCG (175), AFG3L2 (101), ITPR1 (91), STUB1 (77), SPTBN2 (39), or KCNC3 (34). We compared age at onset, disease features, and progression by gene and variant. There were no features that reliably distinguished one of these SCAs from another, and several genes-CACNA1A, ITPR1, SPTBN2, and KCNC3-were associated with both adult-onset and infantile-onset forms of disease, which also differed in presentation. Nevertheless, progression was overall very slow, and STUB1-associated disease was the fastest. Several variants in CACNA1A showed particularly wide ranges in age at onset: one variant produced anything from infantile developmental delay to ataxia onset at 64 years of age within the same family. For CACNA1A, ITPR1, and SPTBN2, the type of variant and charge change on the protein greatly affected the phenotype, defying pathogenicity prediction algorithms. Even with next-generation sequencing, accurate diagnosis requires dialogue between the clinician and the geneticist.
    Keywords:  Spinocerebellar Ataxia, SCA, CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3, onset
    DOI:  https://doi.org/10.1016/j.ajhg.2023.05.009
  21. Free Radic Biol Med. 2023 Jun 12. pii: S0891-5849(23)00493-8. [Epub ahead of print]
    Mitochondrial remodeling and energy metabolism adaptations in colonic crypts during spontaneous epithelial repair after colitis induction in mice.
    Annaïg Lan, Thomas Guerbette, Mireille Andriamihaja, Benjamin Magnin, Martin Bordet, Pierre-Jean Ferron, Agnès Burel, Roselyne Viel, Bernard Fromenty, Anne Corlu, François Blachier, Guillaume Bouguen.
      Mucosal healing has emerged as a therapeutic goal to achieve lasting clinical remission in ulcerative colitis. Intestinal repair in response to inflammation presumably requires higher energy supplies for the restoration of intestinal barrier and physiological functions. However, epithelial energy metabolism during intestinal mucosal healing has been little studied, whereas inflammation-induced alterations have been reported in the main energy production site, the mitochondria. The aim of the present work was to assess the involvement of mitochondrial activity and the events influencing their function during spontaneous epithelial repair after colitis induction in mouse colonic crypts. The results obtained show adaptations of colonocyte metabolism during colitis to ensure maximal ATP production for supporting energetic demand by both oxidative phosphorylation and glycolysis in a context of decreased mitochondrial biogenesis and through mitochondrial function restoration during colon epithelial repair. In parallel, colitis-induced mitochondrial ROS production in colonic epithelial cells was rapidly associated with transient expression of GSH-related enzymes. Mitochondrial respiration in colonic crypts was markedly increased during both inflammatory and recovery phases despite decreased expression of several mitochondrial respiratory chain complex subunits after colitis induction. Rapid induction of mitochondrial fusion was associated with mitochondrial function restoration. Finally, in contrast with the kinetics expression of genes involved in mitochondrial oxidative metabolism and in glycolysis, the expression of glutaminase was markedly reduced in the colonic crypts both during colitis and repair phases. Overall, our data suggest that the epithelial repair after colitis induction is characterized by a rapid and transient increased capacity for mitochondrial ATP production in a context of apparent restoration of mitochondrial biogenesis and metabolic reorientation of energy production. The potential implication of energy production adaptations within colonic crypts to sustain mucosal healing in a context of altered fuel supply is discussed.
    Keywords:  Colon epithelium; DSS-Induced colitis; Mitochondrial respiration and dynamics; Oxidative stress response; Spontaneous epithelial repair
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.06.007
  22. Nat Biotechnol. 2023 Jun;41(6): 739
    First herpesvirus gene therapy.
      
    DOI:  https://doi.org/10.1038/s41587-023-01835-3
  23. Autophagy. 2023 Jun 12. 1-3
    PHAF1/MYTHO is a novel autophagy regulator that controls muscle integrity.
    Anais Franco-Romero, Jean Philippe Leduc-Gaudet, Sabah Na Hussain, Gilles Gouspillou, Marco Sandri.
      Skeletal muscles play key roles in movement, posture, thermogenesis, and whole-body metabolism. Autophagy plays essential roles in the regulation of muscle mass, function and integrity. However, the molecular machinery that regulates autophagy is still incompletely understood. In our recent study, we identified and characterized a novel Forkhead Box O (FoxO)-dependent gene, PHAF1/MYTHO (phagophore assembly factor 1/macro-autophagy and youth optimizer), as a novel autophagy regulator that controls muscle integrity. MYTHO/PHAF1 is upregulated in multiple conditions leading to muscle atrophy, and downregulation of its expression spares muscle atrophy triggered by fasting, denervation, cachexia and sepsis. Overexpression of PHAF1/MYTHO is sufficient to induce muscle atrophy. Prolonged downregulation of PHAF1/MYTHO causes a severe myopathic phenotype, which is characterized by impaired autophagy, muscle weakness, myofiber degeneration, mammalian target of rapamycin complex 1 (mTORC1) hyperactivation and extensive ultrastructural defects, such as accumulation of proteinaceous and membranous structures and tubular aggregates. This myopathic phenotype is attenuated upon administration of the mTORC1 inhibitor rapamycin. These findings position PHAF1/MYTHO as a novel regulator of skeletal muscle autophagy and tissue integrity.
    Keywords:  FoxO; Myopathy; autophagy; mTOR; muscle atrophy; myotonic dystrophy type 1
    DOI:  https://doi.org/10.1080/15548627.2023.2224206
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