bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022‒09‒04
thirty papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico
  1. The human mitochondrial genome contains a second light strand promoter.
  2. Fission impossible: Mitochondrial dynamics direct muscle stem cell fates.
  3. Structural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA.
  4. The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence.
  5. Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.
  6. Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy.
  7. Impact of measuring heteroplasmy of a pathogenic mitochondrial DNA variant at the single-cell level in individuals with mitochondrial disease.
  8. Lip cyanosis as the first symptom of Leigh syndrome associated with mitochondrial complex I deficiency due to a compound heterozygous NDUFS1 mutation: A case report.
  9. Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects.
  10. Bi-Allelic COQ4 Variants Cause Adult-Onset Ataxia-Spasticity Spectrum Disease.
  11. Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy.
  12. Myocardial disturbances of intermediary metabolism in Barth syndrome.
  13. Mitochondrial Medicine: A Promising Therapeutic Option Against Various Neurodegenerative Disorders.
  14. Identifying trajectories of fatigue in patients with primary mitochondrial disease due to the m.3243A > G variant.
  15. Disruption of the VAPB-PTPIP51 ER-mitochondria tethering proteins in post-mortem human amyotrophic lateral sclerosis.
  16. A novel splice variant of Elp3/Kat9 regulates mitochondrial tRNA modification and function.
  17. Functional characterization of two variants of mitochondrial topoisomerase TOP1MT that impact regulation of the mitochondrial genome.
  18. TRIT1 defect leads to a recognizable phenotype of myoclonic epilepsy, speech delay, strabismus, progressive spasticity and normal lactate levels.
  19. SIRT3 regulates mitochondrial biogenesis in aging-related diseases.
  20. Branched-chain amino acids and mitochondrial biogenesis: an overview and mechanistic summary.
  21. Research progress on the pharmacological effects of berberine targeting mitochondria.
  22. DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy.
  23. Case report: A double pathogenic mutation in a patient with late-onset MELAS/PEO overlap syndrome.
  24. The therapeutic prospects and challenges of human neural stem cells for the treatment of Alzheimer's Disease.
  25. Perspectives on current models of Friedreich's ataxia.
  26. Comorbidities in Friedreich ataxia: incidence and manifestations from early to advanced disease stages.
  27. Huntington's disease phenotypes are improved via mTORC1 modulation by small molecule therapy.
  28. Structural insights into crista junction formation by the Mic60-Mic19 complex.
  29. Roles of microglial mitophagy in neurological disorders.
  30. Derivation and culturing of neural stem cells from human embryonic brain tissue.
  1. Mol Cell. 2022 Aug 23. pii: S1097-2765(22)00764-X. [Epub ahead of print]
    The human mitochondrial genome contains a second light strand promoter.
    Benedict G Tan, Christian D Mutti, Yonghong Shi, Xie Xie, Xuefeng Zhu, Pedro Silva-Pinheiro, Katja E Menger, Héctor Díaz-Maldonado, Wei Wei, Thomas J Nicholls, Patrick F Chinnery, Michal Minczuk, Maria Falkenberg, Claes M Gustafsson.
      The human mitochondrial genome must be replicated and expressed in a timely manner to maintain energy metabolism and supply cells with adequate levels of adenosine triphosphate. Central to this process is the idea that replication primers and gene products both arise via transcription from a single light strand promoter (LSP) such that primer formation can influence gene expression, with no consensus as to how this is regulated. Here, we report the discovery of a second light strand promoter (LSP2) in humans, with features characteristic of a bona fide mitochondrial promoter. We propose that the position of LSP2 on the mitochondrial genome allows replication and gene expression to be orchestrated from two distinct sites, which expands our long-held understanding of mitochondrial gene expression in humans.
    Keywords:  DdCBE; LSP2; POLRMT; light strand promoter; mitochondria; mitochondrial DNA; mitochondrial gene expression; mitochondrial promoter; mtDNA; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.011
  2. Cell Stem Cell. 2022 Sep 01. pii: S1934-5909(22)00346-0. [Epub ahead of print]29(9): 1287-1289
    Fission impossible: Mitochondrial dynamics direct muscle stem cell fates.
    Ji-Hyung Lee, Foteini Mourkioti.
      Muscle stem cells (MuSCs) exhibit different metabolic profiles depending on their activity, however the mechanisms by which mitochondria affect MuSC fate has been understudied. In this issue of Cell Stem Cell, Hong et al. (2022) and Baker et al. (2022) demonstrate that defects in mitochondrial dynamics hinder proper MuSC activation and impair muscle regeneration.
    DOI:  https://doi.org/10.1016/j.stem.2022.08.010
  3. Nat Commun. 2022 Aug 30. 13(1): 5100
    Structural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA.
    Bernhard Kuhle, Marscha Hirschi, Lili K Doerfel, Gabriel C Lander, Paul Schimmel.
      Human mitochondrial gene expression relies on the specific recognition and aminoacylation of mitochondrial tRNAs (mtRNAs) by nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs). Despite their essential role in cellular energy homeostasis, strong mutation pressure and genetic drift have led to an unparalleled sequence erosion of animal mtRNAs. The structural and functional consequences of this erosion are not understood. Here, we present cryo-EM structures of the human mitochondrial seryl-tRNA synthetase (mSerRS) in complex with mtRNASer(GCU). These structures reveal a unique mechanism of substrate recognition and aminoacylation. The mtRNASer(GCU) is highly degenerated, having lost the entire D-arm, tertiary core, and stable L-shaped fold that define canonical tRNAs. Instead, mtRNASer(GCU) evolved unique structural innovations, including a radically altered T-arm topology that serves as critical identity determinant in an unusual shape-selective readout mechanism by mSerRS. Our results provide a molecular framework to understand the principles of mito-nuclear co-evolution and specialized mechanisms of tRNA recognition in mammalian mitochondrial gene expression.
    DOI:  https://doi.org/10.1038/s41467-022-32544-1
  4. Orphanet J Rare Dis. 2022 Sep 02. 17(1): 335
    The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence.
    Allison Hanaford, Simon C Johnson.
      BACKGROUND: Genetic mitochondrial diseases represent a significant challenge to human health. These diseases are extraordinarily heterogeneous in clinical presentation and genetic origin, and often involve multi-system disease with severe progressive symptoms. Mitochondrial diseases represent the most common cause of inherited metabolic disorders and one of the most common causes of inherited neurologic diseases, yet no proven therapeutic strategies yet exist. The basic cell and molecular mechanisms underlying the pathogenesis of mitochondrial diseases have not been resolved, hampering efforts to develop therapeutic agents.MAIN BODY: In recent pre-clinical work, we have shown that pharmacologic agents targeting the immune system can prevent disease in the Ndufs4(KO) model of Leigh syndrome, indicating that the immune system plays a causal role in the pathogenesis of at least this form of mitochondrial disease. Intriguingly, a number of case reports have indicated that immune-targeting therapeutics may be beneficial in the setting of genetic mitochondrial disease. Here, we summarize clinical and pre-clinical evidence suggesting a key role for the immune system in mediating the pathogenesis of at least some forms of genetic mitochondrial disease.
    CONCLUSIONS: Significant clinical and pre-clinical evidence indicates a key role for the immune system as a significant in the pathogenesis of at least some forms of genetic mitochondrial disease.
    Keywords:  Genetic disease; Immunity; Leigh syndrome; MELAS; Mitochondrial disease
    DOI:  https://doi.org/10.1186/s13023-022-02495-3
  5. Am J Hum Genet. 2022 Sep 01. pii: S0002-9297(22)00311-1. [Epub ahead of print]109(9): 1692-1712
    Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement.
    Rauan Kaiyrzhanov, Sami E M Mohammed, Reza Maroofian, Ralf A Husain, Alessia Catania, Alessandra Torraco, Ahmad Alahmad, Marina Dutra-Clarke, Sabine Grønborg, Annapurna Sudarsanam, Julie Vogt, Filippo Arrigoni, Julia Baptista, Shahzad Haider, René G Feichtinger, Paolo Bernardi, Alessandra Zulian, Mirjana Gusic, Stephanie Efthymiou, Renkui Bai, Farah Bibi, Alejandro Horga, Julian A Martinez-Agosto, Amanda Lam, Andreea Manole, Diego-Perez Rodriguez, Romina Durigon, Angela Pyle, Buthaina Albash, Carlo Dionisi-Vici, David Murphy, Diego Martinelli, Enrico Bugiardini, Katrina Allis, Costanza Lamperti, Siegfried Reipert, Lotte Risom, Lucia Laugwitz, Michela Di Nottia, Robert McFarland, Laura Vilarinho, Michael Hanna, Holger Prokisch, Johannes A Mayr, Enrico Silvio Bertini, Daniele Ghezzi, Elsebet Østergaard, Saskia B Wortmann, Rosalba Carrozzo, Tobias B Haack, Robert W Taylor, Antonella Spinazzola, Karin Nowikovsky, Henry Houlden.
      Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K+/H+ exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K+ efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial pathologies.
    Keywords:  LETM1; Wolf-Hirschhorn syndrome; genetics; mitochondria; mitochondrial diseases; neurodegeneration; neurology; oxidative phosphorylation; potassium transport; volume homeostasis
    DOI:  https://doi.org/10.1016/j.ajhg.2022.07.007
  6. Hum Mutat. 2022 Aug 28.
    Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy.
    Rocio Rius, Neal K Bennett, Kaustuv Bhattacharya, Lisa G Riley, Zafer Yüksel, Luke E Formosa, Alison G Compton, Russell C Dale, Mark J Cowley, Velimir Gayevskiy, Saeed Al Tala, Abdulrahman A Almehery, Michael T Ryan, David R Thorburn, Ken Nakamura, John Christodoulou.
      Primary mitochondrial diseases are a group of genetically and clinically heterogeneous disorders resulting from oxidative phosphorylation (OXPHOS) defects. COX11 encodes a copper chaperone that participates in the assembly of complex IV (CIV) and has not been previously linked to human disease. In a previous study, we identified that COX11 knockdown decreased cellular ATP derived from respiration, and that ATP levels could be restored with CoQ10 supplementation. This finding is surprising since COX11 has no known role in CoQ10 biosynthesis. Here, we report a novel gene-disease association by identifying biallelic pathogenic variants in COX11 associated with infantile-onset mitochondrial encephalopathies in two unrelated families using trio genome and exome sequencing. Functional studies showed that mutant COX11 fibroblasts had decreased ATP levels which could be rescued by CoQ10 . These results not only suggest that COX11 variants cause defects in energy production but reveal a potential metabolic therapeutic strategy for patients with COX11 variants. This article is protected by copyright. All rights reserved.
    Keywords:  COX11; Coenzyme Q; OXPHOS; mitochondrial disorders
    DOI:  https://doi.org/10.1002/humu.24453
  7. J Inherit Metab Dis. 2022 Aug 13.
    Impact of measuring heteroplasmy of a pathogenic mitochondrial DNA variant at the single-cell level in individuals with mitochondrial disease.
    Atsuko Imai-Okazaki, Kazuhiro R Nitta, Yukiko Yatsuka, Ayumu Sugiura, Masato Arao, Masaru Shimura, Tomohiro Ebihara, Takanori Onuki, Keiko Ichimoto, Akira Ohtake, Kei Murayama, Yasushi Okazaki.
      Pathogenic mitochondrial DNA heteroplasmy has mainly been assessed with bulk sequencing in individuals with mitochondrial disease. However, the distribution of heteroplasmy at the single-cell level in skin fibroblasts obtained from individuals, together with detailed clinical and biochemical information, remains to be investigated. We used the mitochondrial DNA single-cell assay for the transposase-accessible chromatin sequencing method. Skin fibroblasts were obtained from six individuals with mitochondrial disease and pathogenic m.3243A>G variants of differing severity. Different distributions of heteroplasmy at the single-cell level were identified in skin fibroblasts from all six individuals. Four individuals with different outcomes showed similar averaged heteroplasmy rates with normal mitochondrial respiratory chain enzyme activity, while the distribution of single-cell heteroplasmy patterns differed among the individuals. This study showed different heteroplasmy distribution patterns at the single-cell level in individuals with the m.3243A>G variant, who had a similar averaged heteroplasmy rates with normal mitochondrial respiratory chain enzyme activity. Whether such different heteroplasmy distribution patterns explain the different clinical outcomes should be assessed further in future studies. Measuring heteroplasmy of pathogenic mitochondrial DNA variants at the single-cell level could be important in individuals with mitochondrial disease.
    Keywords:  ATAC-seq; heteroplasmy; mitochondrial DNA; mitochondrial disease; single cell
    DOI:  https://doi.org/10.1002/jimd.12547
  8. Medicine (Baltimore). 2022 Aug 26. 101(34): e30303
    Lip cyanosis as the first symptom of Leigh syndrome associated with mitochondrial complex I deficiency due to a compound heterozygous NDUFS1 mutation: A case report.
    Lina Men, Jinxing Feng, Weimin Huang, Mingguo Xu, Xiaoli Zhao, Ruixin Sun, Jianfang Xu, Liming Cao.
      BACKGROUND: Leigh syndrome (LS) is a rare, progressive, and fatal neurodegenerative disease that occurs mainly in infants and children. Neonatal LS has not yet been fully described.METHODS: The study design was approved by the ethics review board of Shenzhen Children's Hospital.
    RESULTS: A 24-day-old full-term male infant presented with a 2-day history of lip cyanosis when crying in September 2021. He was born to nonconsanguineous Asian parents. After birth, the patient was fed poorly. A recurrent decrease in peripheral oxygen saturation and difficulty in weaning from mechanical ventilation during hospitalization were observed. There were no abnormalities on brain magnetic resonance imaging (MRI) or blood and urine organic acid analyses on admission. His lactic acid level increased markedly, and repeat MRI showed symmetrical abnormal signal areas in the bilateral basal ganglia and brainstem with disease progression. Trio whole-exome sequencing revealed 2 heterozygous mutations (c.64C > T [p.R22X] and c.584T > C [p.L195S]) in NDUFS1. Based on these findings, mitochondrial respiratory chain complex I deficiency-related LS was diagnosed. The patient underwent tracheal intubation and mechanical ventilation for respiratory failure. His oxygen saturation levels were maintained at normal levels with partially assisted ventilation. He was administered broad-spectrum antibiotics, oral coenzyme Q10, multivitamins, and idebenone. During hospitalization, the patient developed progressive consciousness impairment and respiratory and circulatory failure. He died on day 30.
    CONCLUSION: Lip cyanosis is an important initial symptom in LS. Mild upper respiratory tract infections can induce LS and aggravate the disease. No abnormal changes in the brain MRI were observed in the early LS stages in this patient. Multiple MRIs and blood lactic acid tests during disease progression and genetic testing are important for prompt and accurate diagnosis of LS.
    DOI:  https://doi.org/10.1097/MD.0000000000030303
  9. Front Mol Biosci. 2022 ;9 890653
    Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects.
    Madleen Zighan, David Arkadir, Liza Douiev, Guy Keller, Chaya Miller, Ann Saada.
      Omaveloxolone (RTA408) is a second-generation oleanane triterpenoid Nrf2 inducer with antioxidant and anti-inflammatory properties and was reported to improve mitochondrial bioenergetics. It is currently being tested in medical trials for Friedrich ataxia, a genetic, multi-organ disease involving mitochondrial dysfunction. Thus, omaveloxolone could potentially be beneficial for additional disorders involving mitochondrial dysfunction. To this end, we investigated its effect on primary fibroblasts derived from patients with mitochondrial complex I deficiency, mitochondrial cytochrome oxidase deficiency, and two recessive forms of Parkinson's disease. Patients and control cells were incubated in the presence or absence of 50 nM omaveloxolone for 72 h prior to measurements. Generally, growth on galactose medium and ATP production were unaltered. Mitochondrial membrane potential was slightly but significantly decreased, while reactive oxygen species (ROS) production was variably decreased. Mitochondrial mass and mitochondrial DNA (mtDNA) contents were significantly increased in the patient's cells. These results were partially confirmed by the results of oxygen consumption studies which disclosed increased maximal oxygen consumption rates in most cells and increased energy status in all treated cells. Further investigation is required to explore the precise effect of omaveloxolone on mitochondrial function in disease.
    Keywords:  Omavleoxolone RTA408; Parkinson’s disease; ROS; fibroblasts; mitochondria; mitochondrial disease
    DOI:  https://doi.org/10.3389/fmolb.2022.890653
  10. Mov Disord. 2022 Sep 01.
    Bi-Allelic COQ4 Variants Cause Adult-Onset Ataxia-Spasticity Spectrum Disease.
    Isabell Cordts, Luisa Semmler, Jannik Prasuhn, Annette Seibt, Diran Herebian, Tharsini Navaratnarajah, Joohyun Park, Natalie Deininger, Lucia Laugwitz, Sophia L Göricke, Paul Lingor, Norbert Brüggemann, Alexander Münchau, Matthis Synofzik, Dagmar Timmann, Johannes A Mayr, Tobias B Haack, Felix Distelmaier, Marcus Deschauer.
      BACKGROUND: COQ4 codes for a mitochondrial protein required for coenzyme Q10 (CoQ10 ) biosynthesis. Autosomal recessive COQ4-associated CoQ10 deficiency leads to an early-onset mitochondrial multi-organ disorder.METHODS: In-house exome and genome datasets (n = 14,303) were screened for patients with bi-allelic variants in COQ4. Work-up included clinical characterization and functional studies in patient-derived cell lines.
    RESULTS: Six different COQ4 variants, three of them novel, were identified in six adult patients from four different families. Three patients had a phenotype of hereditary spastic paraparesis, two sisters showed a predominant cerebellar ataxia, and one patient had mild signs of both. Studies in patient-derived fibroblast lines revealed significantly reduced amounts of COQ4 protein, decreased CoQ10 concentrations, and elevated levels of the metabolic intermediate 6-demethoxyubiquinone.
    CONCLUSION: We report bi-allelic variants in COQ4 causing an adult-onset ataxia-spasticity spectrum phenotype and a disease course much milder than previously reported. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  cerebellar ataxia; coenzyme Q10 deficiency; hereditary spastic paraplegia; mitochondriopathy
    DOI:  https://doi.org/10.1002/mds.29167
  11. Nat Commun. 2022 Sep 02. 13(1): 5164
    Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy.
    Jonas Benjamin Michaelis, Melinda Elaine Brunstein, Süleyman Bozkurt, Ludovico Alves, Martin Wegner, Manuel Kaulich, Christian Pohl, Christian Münch.
      Mitophagy is essential to maintain mitochondrial function and prevent diseases. It activates upon mitochondria depolarization, which causes PINK1 stabilization on the mitochondrial outer membrane. Strikingly, a number of conditions, including mitochondrial protein misfolding, can induce mitophagy without a loss in membrane potential. The underlying molecular details remain unclear. Here, we report that a loss of mitochondrial protein import, mediated by the pre-sequence translocase-associated motor complex PAM, is sufficient to induce mitophagy in polarized mitochondria. A genome-wide CRISPR/Cas9 screen for mitophagy inducers identifies components of the PAM complex. Protein import defects are able to induce mitophagy without a need for depolarization. Upon mitochondrial protein misfolding, PAM dissociates from the import machinery resulting in decreased protein import and mitophagy induction. Our findings extend the current mitophagy model to explain mitophagy induction upon conditions that do not affect membrane polarization, such as mitochondrial protein misfolding.
    DOI:  https://doi.org/10.1038/s41467-022-32564-x
  12. Front Cardiovasc Med. 2022 ;9 981972
    Myocardial disturbances of intermediary metabolism in Barth syndrome.
    Amanda A Greenwell, Seyed Amirhossein Tabatabaei Dakhili, John R Ussher.
      Barth Syndrome (BTHS) is a rare X-linked mitochondrial disorder due to mutations in the gene TAFAZZIN, which leads to immature cardiolipin (CL) remodeling and is characterized by the development of cardiomyopathy. The immature CL remodeling in BTHS results in electron transport chain respiratory defects and destabilization of supercomplexes, thereby impairing ATP production. Thus, BTHS-related cardiomyopathy appears to share metabolic characteristics of the failing heart being an "engine out of fuel." As CL associates with numerous mitochondrial enzymes involved in ATP production, BTHS is also characterized by several defects in intermediary energy metabolism. Herein we will describe the primary disturbances in intermediary energy metabolism relating to the heart's major fuel sources, fatty acids, carbohydrates, ketones, and amino acids. In addition, we will interrogate whether these disturbances represent potential metabolic targets for alleviating BTHS-related cardiomyopathy.
    Keywords:  Barth syndrome (BTHS); cardiac energetics; cardiomyopathy; fatty acid oxidation; glucose oxidation; ketone oxidation
    DOI:  https://doi.org/10.3389/fcvm.2022.981972
  13. Curr Neuropharmacol. 2022 Aug 30.
    Mitochondrial Medicine: A Promising Therapeutic Option Against Various Neurodegenerative Disorders.
    Mohannad A Almikhlafi, Mohammed M Karami, Ankit Jana, Thamer M Alqurashi, Mohammed Majrashi, Badrah S Alghamdi, Ghulam Md Ashraf.
      Abnormal mitochondrial morphology and metabolic dysfunction have been observed in many neurodegenerative disorders (NDDs). Mitochondrial dysfunction can be caused by aberrant mitochondrial DNA, mutant nuclear proteins that interact with mitochondria directly or indirectly, or unknown reasons. Since mitochondria play a significant role in neurodegeneration, mitochondria- targeted therapies represent a prosperous direction for the development of novel drug compounds that can be used to treat NDDs. This review gives a brief description of how mitochondrial abnormalities lead to various NDDs such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We further explore the promising therapeutic effectiveness of mitochondria-directed antioxidants, MitoQ, MitoVitE, MitoPBN, and dimebon. We have also discussed the possibility of mitochondrial gene therapy as a therapeutic option for these NDDs.
    Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Gene therapy; Huntington’s disease; Mitochondrial dysfunction; Parkinson’s disease.
    DOI:  https://doi.org/10.2174/1570159X20666220830112408
  14. J Inherit Metab Dis. 2022 Aug 13.
    Identifying trajectories of fatigue in patients with primary mitochondrial disease due to the m.3243A > G variant.
    Inge-Lot Klein, Christianne M Verhaak, Jan A M Smeitink, Paul de Laat, Mirian C H Janssen, José A E Custers.
      Severe fatigue is a common complaint in patients with primary mitochondrial disease. However, less is known about the course of fatigue over time. This longitudinal observational cohort study of patients with the mitochondrial DNA 3243 A>G variant explored trajectories of fatigue over 2 years, and characteristics of patients within these fatigue trajectories. Fifty-three adult patients treated at the Radboud University Medical Center Nijmegen were included. The majority of the patients reported consistent, severe fatigue (41%), followed by patients with a mixed pattern of severe and mild fatigue (36%). Then, 23% of patients reported stable mild fatigue levels. Patients with a stable high fatigue trajectory were characterized by higher disease manifestations scores, more clinically relevant mental health symptoms, and lower psychosocial functioning and quality of life compared to patients reporting stable low fatigue levels. Fatigue at baseline and disease manifestation scores predicted fatigue severity at the 2-year assessment (57% explained variance). This study demonstrates that severe fatigue is a common and stable complaint in the majority of patients. Clinicians should be aware of severe fatigue in patients with moderate to severe disease manifestation scores on the Newcastle Mitochondrial Disease Scale, the high prevalence of clinically relevant mental health symptoms and overall impact on quality of life in these patients. Screening of fatigue and psychosocial variables will guide suitable individualized treatment to improve the quality of life.
    Keywords:  fatigue; longitudinal; mental health; mitochondrial disease; mtDNA 3243A>G variant; quality of life
    DOI:  https://doi.org/10.1002/jimd.12546
  15. Front Cell Dev Biol. 2022 ;10 950767
    Disruption of the VAPB-PTPIP51 ER-mitochondria tethering proteins in post-mortem human amyotrophic lateral sclerosis.
    Naomi Hartopp, Dawn H W Lau, Sandra M Martin-Guerrero, Andrea Markovinovic, Gábor M Mórotz, Jenny Greig, Elizabeth B Glennon, Claire Troakes, Patricia Gomez-Suaga, Wendy Noble, Christopher C J Miller.
      Signaling between the endoplasmic reticulum (ER) and mitochondria regulates many neuronal functions that are perturbed in amyotrophic lateral sclerosis (ALS) and perturbation to ER-mitochondria signaling is seen in cell and transgenic models of ALS. However, there is currently little evidence that ER-mitochondria signaling is altered in human ALS. ER-mitochondria signaling is mediated by interactions between the integral ER protein VAPB and the outer mitochondrial membrane protein PTPIP51 which act to recruit and "tether" regions of ER to the mitochondrial surface. The VAPB-PTPI51 tethers are now known to regulate a number of ER-mitochondria signaling functions. These include delivery of Ca2+ from ER stores to mitochondria, mitochondrial ATP production, autophagy and synaptic activity. Here we investigate the VAPB-PTPIP51 tethers in post-mortem control and ALS spinal cords. We show that VAPB protein levels are reduced in ALS. Proximity ligation assays were then used to quantify the VAPB-PTPIP51 interaction in spinal cord motor neurons in control and ALS cases. These studies revealed that the VAPB-PTPIP51 tethers are disrupted in ALS. Thus, we identify a new pathogenic event in post-mortem ALS.
    Keywords:  PTPIP51; VAPB; amyotrophic lateral sclerosis; endoplasmic reticulum; mitochondria
    DOI:  https://doi.org/10.3389/fcell.2022.950767
  16. Sci Rep. 2022 Aug 31. 12(1): 14804
    A novel splice variant of Elp3/Kat9 regulates mitochondrial tRNA modification and function.
    Rachid Boutoual, Hyunsun Jo, Indra Heckenbach, Ritesh Tiwari, Herbert Kasler, Chad A Lerner, Samah Shah, Birgit Schilling, Vincenzo Calvanese, Matthew J Rardin, Morten Scheibye-Knudsen, Eric Verdin.
      Post-translational modifications, such as lysine acetylation, regulate the activity of diverse proteins across many cellular compartments. Protein deacetylation in mitochondria is catalyzed by the enzymatic activity of the NAD+-dependent deacetylase sirtuin 3 (SIRT3), however it remains unclear whether corresponding mitochondrial acetyltransferases exist. We used a bioinformatics approach to search for mitochondrial proteins with an acetyltransferase catalytic domain, and identified a novel splice variant of ELP3 (mt-ELP3) of the elongator complex, which localizes to the mitochondrial matrix in mammalian cells. Unexpectedly, mt-ELP3 does not mediate mitochondrial protein acetylation but instead induces a post-transcriptional modification of mitochondrial-transfer RNAs (mt-tRNAs). Overexpression of mt-ELP3 leads to the protection of mt-tRNAs against the tRNA-specific RNase angiogenin, increases mitochondrial translation, and furthermore increases expression of OXPHOS complexes. This study thus identifies mt-ELP3 as a non-canonical mt-tRNA modifying enzyme.
    DOI:  https://doi.org/10.1038/s41598-022-18114-x
  17. J Biol Chem. 2022 Aug 24. pii: S0021-9258(22)00863-8. [Epub ahead of print] 102420
    Functional characterization of two variants of mitochondrial topoisomerase TOP1MT that impact regulation of the mitochondrial genome.
    Iman Al Khatib, Jingti Deng, Andrew Symes, Marina Kerr, Hongliang Zhang, Sharyin Huang, Yves Pommier, Aneal Khan, Timothy E Shutt.
      TOP1MT encodes a mitochondrial topoisomerase that is important for mtDNA regulation, and is involved in mitochondrial replication, transcription, and translation. Two variants predicted to affect TOP1MT function (V1 - R198C and V2 - V338L) were identified by exome sequencing of a newborn with hypertrophic cardiomyopathy. As no pathogenic TOP1MT variants had been confirmed previously, we characterized these variants for their ability to rescue several TOP1MT functions in knockout cells. Consistent with these TOP1MT variants contributing to the patient phenotype, our comprehensive characterization suggests that both variants had impaired activity. Critically, we determined neither variant was able to restore steady state levels of mitochondrial-encoded proteins, nor to rescue oxidative phosphorylation when re-expressed in TOP1MT knockout cells. However, we found the two variants behaved differently in some respects; while the V1 variant was more efficient in restoring transcript levels, the V2 variant showed better rescue of mtDNA copy number and replication. These findings suggest that the different TOP1MT variants affect distinct TOP1MT functions. Altogether, these findings begin to provide insight into the many roles that TOP1MT plays in the maintenance and expression of the mitochondrial genome, and how impairments in this important protein may lead to human pathology.
    Keywords:  TOP1MT; mitochondria; mtDNA; replication; transcription; translation
    DOI:  https://doi.org/10.1016/j.jbc.2022.102420
  18. J Inherit Metab Dis. 2022 Sep 01.
    TRIT1 defect leads to a recognizable phenotype of myoclonic epilepsy, speech delay, strabismus, progressive spasticity and normal lactate levels.
    Ewout Muylle, Huafang Jiang, Christin Johnsen, Seul Kee Byeon, Wasantha Ranatunga, Kishore Garapati, Roman M Zenka, Graeme Preston, Akhilesh Pandey, Tamas Kozicz, Fang Fang, Eva Morava.
      TRIT1 defect is a rare, autosomal-recessive disorder of transcription, initially described as a condition with developmental delay, myoclonic seizures and abnormal mitochondrial function. Currently, only thirteen patients have been reported. We reviewed the genetic, clinical and metabolic aspects of the disease in all known patients, including two novel, unrelated TRIT1 cases with abnormalities in oxidative phosphorylation complexes I and IV in fibroblasts. Taken together the features of all fifteen patients, TRIT1 defect could be identified as a potentially recognizable syndrome including myoclonic epilepsy, speech delay, strabismus, progressive spasticity and variable microcephaly, with normal lactate levels. Half of the patients had oxidative phosphorylation complex measurements and had multiple complex abnormalities.
    Keywords:  OXPHOS; lipidomics; mitochondrial tRNA; myoclonic seizures; spasticity
    DOI:  https://doi.org/10.1002/jimd.12550
  19. J Biomed Res. 2022 Jun 28. 1-12
    SIRT3 regulates mitochondrial biogenesis in aging-related diseases.
    Hong-Yan Li, Zhi-You Cai.
      Sirtuin 3 (SIRT3), the main family member of mitochondrial deacetylase, targets the majority of substrates controlling mitochondrial biogenesis via lysine deacetylation and modulates important cellular functions such as energy metabolism, reactive oxygen species production and clearance, oxidative stress, and aging. Deletion of SIRT3 has a deleterious effect on mitochondrial biogenesis, thus leading to the defect in mitochondrial function and insufficient ATP production. Imbalance of mitochondrial dynamics leads to excessive mitochondrial biogenesis, dampening mitochondrial function. Mitochondrial dysfunction plays an important role in several diseases related to aging, such as cardiovascular disease, cancer and neurodegenerative diseases. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) launches mitochondrial biogenesis through activating nuclear respiratory factors. These factors act on genes, transcribing and translating mitochondrial DNA to generate new mitochondria. PGC1α builds a bridge between SIRT3 and mitochondrial biogenesis. This review described the involvement of SIRT3 and mitochondrial dynamics, particularly mitochondrial biogenesis in aging-related diseases, and further illustrated the role of the signaling events between SIRT3 and mitochondrial biogenesis in the pathological process of aging-related diseases.
    Keywords:  PGC1α; SIRT3; aging-related diseases; mitochondrial biogenesis
    DOI:  https://doi.org/10.7555/JBR.36.20220078
  20. Mol Nutr Food Res. 2022 Sep 01. e2200109
    Branched-chain amino acids and mitochondrial biogenesis: an overview and mechanistic summary.
    Jason S Hinkle, Caroline N Rivera, Roger A Vaughan.
      Branched-chain amino acids (BCAA) are essential in the diet and promote several vital cell responses which may have benefits for health and athletic performance, as well as disease prevention. While BCAA are well-known for their ability to stimulate muscle protein synthesis, their effects on cell energetics are also becoming well-documented, but these receive less attention. In this review, we highlight much of the current evidence demonstrating BCAA ability (as individual amino acids or as part of dietary mixtures) to alter regulators of cellular energetics with an emphasis on mitochondrial biogenesis and related signaling. Several studies have shown, both in vitro and in vivo, that BCAA (either individual or as a mixture) may promote signaling associated with increased mitochondrial biogenesis including the upregulation of master regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), as well as numerous downstream targets and related function. However, sparse data in humans and the difficulty of controlling variables associated with feeding studies leaves the physiological relevance of these findings unclear. Future well-controlled diet studies will be needed to assess if BCAA consumption is associated with increased mitochondrial biogenesis and improved metabolic outcomes in healthy and/or diseased human populations. This article is protected by copyright. All rights reserved.
    Keywords:  isoleucine; leucine; mitochondrial biogenesis; skeletal muscle; valine
    DOI:  https://doi.org/10.1002/mnfr.202200109
  21. Front Endocrinol (Lausanne). 2022 ;13 982145
    Research progress on the pharmacological effects of berberine targeting mitochondria.
    Xinyi Fang, Haoran Wu, Jiahua Wei, Runyu Miao, Yanjiao Zhang, Jiaxing Tian.
      Berberine is a natural active ingredient extracted from the rhizome of Rhizoma Coptidis, which interacts with multiple intracellular targets and exhibits a wide range of pharmacological activities. Previous studies have preliminarily confirmed that the regulation of mitochondrial activity is related to various pharmacological actions of berberine, such as regulating blood sugar and lipid and inhibiting tumor progression. However, the mechanism of berberine's regulation of mitochondrial activity remains to be further studied. This paper summarizes the molecular mechanism of the mitochondrial quality control system and briefly reviews the targets of berberine in regulating mitochondrial activity. It is proposed that berberine mainly regulates glycolipid metabolism by regulating mitochondrial respiratory chain function, promotes tumor cell apoptosis by regulating mitochondrial apoptosis pathway, and protects cardiac function by promoting mitophagy to alleviate mitochondrial dysfunction. It reveals the mechanism of berberine's pharmacological effects from the perspective of mitochondria and provides a scientific basis for the application of berberine in the clinical treatment of diseases.
    Keywords:  berberine; cardiovascular diseases; glycolipid metabolism disorder; mitochondria; pharmacological action; tumor
    DOI:  https://doi.org/10.3389/fendo.2022.982145
  22. Brain. 2022 Aug 30. pii: awac313. [Epub ahead of print]
    DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy.
    Dorien Imberechts, Inge Kinnart, Fieke Wauters, Joanne Terbeek, Liselot Manders, Keimpe Wierda, Kristel Eggermont, Rodrigo Furtado Madeiro, Carolyn Sue, Catherine Verfaillie, Wim Vandenberghe.
      Loss-of-function mutations in the PRKN, PINK1 and PARK7 genes (encoding parkin, PINK1 and DJ-1, respectively) cause autosomal recessive forms of Parkinson's disease. PINK1 and parkin jointly mediate selective autophagy of damaged mitochondria (mitophagy), but the mechanisms by which loss of DJ-1 induces Parkinson's disease, are not well understood. Here, we investigated PINK1/parkin-mediated mitophagy in cultured human fibroblasts and iPSC-derived neurons with homozygous PARK7 mutations. We found that DJ-1 is essential for PINK1/parkin-mediated mitophagy. Loss of DJ-1 did not interfere with PINK1 or parkin activation after mitochondrial depolarization, but blocked mitophagy further downstream by inhibiting recruitment of the selective autophagy receptor optineurin to depolarized mitochondria. By contrast, starvation-induced, non-selective autophagy was not affected by loss of DJ-1. In wild-type fibroblasts and iPSC-derived dopaminergic neurons, endogenous DJ-1 translocated to depolarized mitochondria in close proximity with optineurin. DJ-1 translocation to depolarized mitochondria was dependent on PINK1 and parkin and did not require oxidation of cysteine residue 106 of DJ-1. Overexpression of DJ-1 did not rescue the mitophagy defect of PINK1- or parkin-deficient cells. These findings position DJ-1 downstream of PINK1 and parkin in the same pathway and suggest that disruption of PINK1/parkin/DJ-1-mediated mitophagy is a common pathogenic mechanism in autosomal recessive Parkinson's disease.
    Keywords:  DJ-1; Parkinson’s disease; autophagy; mitophagy; optineurin
    DOI:  https://doi.org/10.1093/brain/awac313
  23. Front Neurol. 2022 ;13 927823
    Case report: A double pathogenic mutation in a patient with late-onset MELAS/PEO overlap syndrome.
    Qiu Yan Zhao, Wen Zhao Zhang, Xue Lian Zhu, Fei Qiao, Li Yuan Jia, Bi Li, Yong Xiao, Han Chen, Yu Zhang, Yun Guo Chen, Yong Liang Wang.
      Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and progressive external ophthalmoplegia (PEO) are established phenotypes of mitochondrial disorders. They are maternally-inherited, multisystem disorder that is characterized by variable clinical, biochemical, and imaging features. We described the clinical and genetic features of a Chinese patient with late-onset MELAS/PEO overlap syndrome, which has rarely been reported. The patient was a 48-year-old woman who presented with recurrent ischemic strokes associated with characteristic brain imaging and bilateral ptosis. We assessed her clinical characteristics and performed mutation analyses. The main manifestations of the patient were stroke-like episodes and seizures. A laboratory examination revealed an increased level of plasma lactic acid and a brain MRI showed multiple lesions in the cortex. A muscle biopsy demonstrated ragged red fibers. Genetic analysis from a muscle sample identified two mutations: TL1 m.3243A>G and POLG c.3560C>T, with mutation loads of 83 and 43%, respectively. This suggested that mitochondrial disorders are associated with various clinical presentations and an overlap between the syndromes and whole exome sequencing is important, as patients may carry multiple mutations.
    Keywords:  Chinese; MELAS; PEO; gene; mutation
    DOI:  https://doi.org/10.3389/fneur.2022.927823
  24. Cell Regen. 2022 Sep 02. 11(1): 28
    The therapeutic prospects and challenges of human neural stem cells for the treatment of Alzheimer's Disease.
    Chunmei Yue, Su Feng, Yingying Chen, Naihe Jing.
      Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder associated with aging. Due to its insidious onset, protracted progression, and unclear pathogenesis, it is considered one of the most obscure and intractable brain disorders, and currently, there are no effective therapies for it. Convincing evidence indicates that the irreversible decline of cognitive abilities in patients coincides with the deterioration and degeneration of neurons and synapses in the AD brain. Human neural stem cells (NSCs) hold the potential to functionally replace lost neurons, reinforce impaired synaptic networks, and repair the damaged AD brain. They have therefore received extensive attention as a possible source of donor cells for cellular replacement therapies for AD. Here, we review the progress in NSC-based transplantation studies in animal models of AD and assess the therapeutic advantages and challenges of human NSCs as donor cells. We then formulate a promising transplantation approach for the treatment of human AD, which would help to explore the disease-modifying cellular therapeutic strategy for the treatment of human AD.
    Keywords:  Alzheimer's disease; Brain disorders; Brain region-specific transplantation; Cognitive ability; Neural subtype-specific transplantation; Stem cell-based replacement therapy
    DOI:  https://doi.org/10.1186/s13619-022-00128-5
  25. Front Cell Dev Biol. 2022 ;10 958398
    Perspectives on current models of Friedreich's ataxia.
    Simge Kelekçi, Abdullah Burak Yıldız, Kenan Sevinç, Deniz Uğurlu Çimen, Tamer Önder.
      Friedreich's ataxia (FRDA, OMIM#229300) is the most common hereditary ataxia, resulting from the reduction of frataxin protein levels due to the expansion of GAA repeats in the first intron of the FXN gene. Why the triplet repeat expansion causes a decrease in Frataxin protein levels is not entirely known. Generation of effective FRDA disease models is crucial for answering questions regarding the pathophysiology of this disease. There have been considerable efforts to generate in vitro and in vivo models of FRDA. In this perspective article, we highlight studies conducted using FRDA animal models, patient-derived materials, and particularly induced pluripotent stem cell (iPSC)-derived models. We discuss the current challenges in using FRDA animal models and patient-derived cells. Additionally, we provide a brief overview of how iPSC-based models of FRDA were used to investigate the main pathways involved in disease progression and to screen for potential therapeutic agents for FRDA. The specific focus of this perspective article is to discuss the outlook and the remaining challenges in the context of FRDA iPSC-based models.
    Keywords:  ataxia; disease model cell; frataxin; iPSC (induced pluripotent stem cell); triplet repeat disease
    DOI:  https://doi.org/10.3389/fcell.2022.958398
  26. Neurol Sci. 2022 Sep 02.
    Comorbidities in Friedreich ataxia: incidence and manifestations from early to advanced disease stages.
    Mario Fichera, Anna Castaldo, Alessia Mongelli, Gloria Marchini, Cinzia Gellera, Lorenzo Nanetti, Caterina Mariotti.
      OBJECTIVES: Friedreich's ataxia (FA) is the most common hereditary ataxia, characterized by multisystemic manifestations including neurological, cardiological, and skeletal abnormalities. In this study, we aimed to analyze the incidences of disease-related and unrelated comorbidities occurring in different stages of the disease progression.METHODS: We analyzed longitudinal data from a 10-year prospective observational study in a cohort of 175 FA patients with disease onset < 25 years. We analyzed the time of diagnosis for the most frequently reported medical conditions, with respect to age and disease duration of each patient.
    RESULTS: In the early stage of the disease, scoliosis (53.3%), hypertrophic cardiomyopathy (46.7%), and pes cavus (33.3%) were the most frequently diagnosed conditions, sometimes occurring even before the onset of ataxia. Diabetes, bone fractures, and depression have the same incidence at all disease stages. In patients with > 20 years of disease duration, the most frequent complications were hearing and visual loss (20% and 26%), arrhythmias (16%), and psychosis (18%). Thirteen patients presented hallucinations/delusions in the absence of neurological acute events or mental illness predisposing to psychotic manifestations. Six of these patients fulfill the diagnostic criteria for Charles Bonnet syndrome.
    CONCLUSIONS: Incidence of FA-related medical conditions varies according to disease duration. In patients with very long disease duration, we observed an unexpectedly high incidence of visual and auditory pseudo-hallucinations that were not previously reported in FA patients. We hypothesized that these late complications may be possibly related to the severe sensory deafferentation syndrome observed in the advanced stages of FA disease.
    Keywords:  Charles Bonnet syndrome; Complications; Deafferentation syndrome; Hallucination; Optic neuropathy; Psychosis
    DOI:  https://doi.org/10.1007/s10072-022-06360-w
  27. PLoS One. 2022 ;17(8): e0273710
    Huntington's disease phenotypes are improved via mTORC1 modulation by small molecule therapy.
    Sophie St-Cyr, Daniel D Child, Emilie Giaime, Alicia R Smith, Christine J Pascua, Seung Hahm, Eddine Saiah, Beverly L Davidson.
      Huntington's Disease (HD) is a dominantly inherited neurodegenerative disease for which the major causes of mortality are neurodegeneration-associated aspiration pneumonia followed by cardiac failure. mTORC1 pathway perturbations are present in HD models and human tissues. Amelioration of mTORC1 deficits by genetic modulation improves disease phenotypes in HD models, is not a viable therapeutic strategy. Here, we assessed a novel small molecule mTORC1 pathway activator, NV-5297, for its improvement of the disease phenotypes in the N171-82Q HD mouse model. Oral dosing of NV-5297 over 6 weeks activated mTORC1, increased striatal volume, improved motor learning and heart contractility. Further, the heart contractility, heart fibrosis, and survival were improved in response to the cardiac stressor isoprenaline when compared to vehicle-treated mice. Cummulatively, these data support mTORC1 activation as a therapeutic target in HD and consolidates NV-5297 as a promising drug candidate for treating central and peripheral HD phenotypes and, more generally, mTORC1-deficit related diseases.
    DOI:  https://doi.org/10.1371/journal.pone.0273710
  28. Sci Adv. 2022 Sep 02. 8(35): eabo4946
    Structural insights into crista junction formation by the Mic60-Mic19 complex.
    Tobias Bock-Bierbaum, Kathrin Funck, Florian Wollweber, Elisa Lisicki, Karina von der Malsburg, Alexander von der Malsburg, Janina Laborenz, Jeffrey K Noel, Manuel Hessenberger, Sibylle Jungbluth, Carola Bernert, Séverine Kunz, Dietmar Riedel, Hauke Lilie, Stefan Jakobs, Martin van der Laan, Oliver Daumke.
      Mitochondrial cristae membranes are the oxidative phosphorylation sites in cells. Crista junctions (CJs) form the highly curved neck regions of cristae and are thought to function as selective entry gates into the cristae space. Little is known about how CJs are generated and maintained. We show that the central coiled-coil (CC) domain of the mitochondrial contact site and cristae organizing system subunit Mic60 forms an elongated, bow tie-shaped tetrameric assembly. Mic19 promotes Mic60 tetramerization via a conserved interface between the Mic60 mitofilin and Mic19 CHCH (CC-helix-CC-helix) domains. Dimerization of mitofilin domains exposes a crescent-shaped membrane-binding site with convex curvature tailored to interact with the curved CJ neck. Our study suggests that the Mic60-Mic19 subcomplex traverses CJs as a molecular strut, thereby controlling CJ architecture and function.
    DOI:  https://doi.org/10.1126/sciadv.abo4946
  29. Front Aging Neurosci. 2022 ;14 979869
    Roles of microglial mitophagy in neurological disorders.
    Yang Liu, Miao Wang, Xiao-Ou Hou, Li-Fang Hu.
      Microglia are the resident innate immune cells in the central nervous system (CNS) that serve as the first line innate immunity in response to pathogen invasion, ischemia and other pathological stimuli. Once activated, they rapidly release a variety of inflammatory cytokines and phagocytose pathogens or cell debris (termed neuroinflammation), which is beneficial for maintaining brain homeostasis if appropriately activated. However, excessive or uncontrolled neuroinflammation may damage neurons and exacerbate the pathologies in neurological disorders. Microglia are highly dynamic cells, dependent on energy supply from mitochondria. Moreover, dysfunctional mitochondria can serve as a signaling platform to facilitate innate immune responses in microglia. Mitophagy is a means of clearing damaged or redundant mitochondria, playing a critical role in the quality control of mitochondrial homeostasis and turnover. Mounting evidence has shown that mitophagy not only limits the inflammatory response in microglia but also affects their phagocytosis, whereas mitochondria dysfunction and mitophagy defects are associated with aging and neurological disorders. Therefore, targeting microglial mitophagy is a promising therapeutic strategy for neurological disorders. This article reviews and highlights the role and regulation of mitophagy in microglia in neurological conditions, and the research progress in manipulating microglial mitophagy and future directions in this field are also discussed.
    Keywords:  microglia; mitochondria; mitophagy; neuroinflammation; neurological disorders
    DOI:  https://doi.org/10.3389/fnagi.2022.979869
  30. STAR Protoc. 2022 Sep 16. 3(3): 101628
    Derivation and culturing of neural stem cells from human embryonic brain tissue.
    Yujin Suk, Agata Kieliszek, Daniel Mobilio, Chitra Venugopal, Sheila K Singh.
      Human neural stem cells (hNSCs) are a valuable tool in brain cancer research since they are used as a normal control for multiple assays, mainly pertaining to toxicity. Here, we present a protocol to safely and successfully derive and culture hNSCs in vitro from human embryonic brain tissue. We describe the steps to dissociate embryonic brain tissue and culture hNSCs, followed by the procedure to expand hNSCs. These cells can be used for downstream applications including RNA-seq and omics studies. For complete details on the use and execution of this protocol, please refer to Venugopal et al. (2012b), Bakhshinyan et al. (2019), and Venugopal et al. (2012a).
    Keywords:  Cell culture; Cell isolation; Developmental biology; Health sciences; Neuroscience; Stem cells
    DOI:  https://doi.org/10.1016/j.xpro.2022.101628
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