bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022–12–18
35 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mitochondrial Dysfunction and Pharmacodynamics of Mitofusin Activation in Murine Charcot-Marie-Tooth Disease Type 2A.
  2. Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines.
  3. Exercise and mitochondrial remodeling to prevent age-related neurodegeneration.
  4. Changing faces of mitochondrial disease: autosomal recessive POLG disease mimicking myasthenia gravis and progressive supranuclear palsy.
  5. An AAA-ATPase links mitochondrial division with DNA nucleoids.
  6. Bilateral Nonsyndromic Sensorineural Hearing Loss Caused by a NARS2 Mutation.
  7. Investigating mitochondrial fission, fusion, and autophagy in retinal pigment epithelium from donors with age-related macular degeneration.
  8. Diversity of mitophagy pathways at a glance.
  9. Methods to Assess the Role of PARPs in Regulating Mitochondrial Oxidative Function.
  10. Nicotinamide Mononucleotide Supplementation Improves Mitochondrial Dysfunction and Rescues Cellular Senescence by NAD+/Sirt3 Pathway in Mesenchymal Stem Cells.
  11. TFAM's Contributions to mtDNA Replication and OXPHOS Biogenesis Are Genetically Separable.
  12. Transcriptomic analyses reveal neuronal specificity of Leigh syndrome associated genes.
  13. Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments.
  14. Safety of lenadogene nolparvovec gene therapy over 5 years in 189 patients with Leber hereditary optic neuropathy.
  15. A mitochondrial trigger for beige adipocyte development.
  16. Neuroimaging in Leber Hereditary Optic Neuropathy: State-of-the-art and future prospects.
  17. Mitochondrial dynamics proteins as emerging drug targets.
  18. PINK1/Parkin-mediated mitophagy in neurodegenerative diseases.
  19. Paternal aging impacts mitochondrial DNA content and telomere length in mouse embryos.
  20. NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy.
  21. Clinical heterogeneity of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome in thirteen palestinian patients and report of a novel variant in the SLC25A15 gene.
  22. Targeting Mitochondrial Dynamics Proteins for the Development of Therapies for Cardiovascular Diseases.
  23. In Utero Exposure to Air Pollutants and Mitochondrial Heteroplasmy in Neonates.
  24. CENP-F-dependent DRP1 function regulates APC/C activity during oocyte meiosis I.
  25. Super-Resolution Microscopy to Study Interorganelle Contact Sites.
  26. Efficacy and Safety of Leriglitazone in Patients With Friedreich Ataxia: A Phase 2 Double-Blind, Randomized Controlled Trial (FRAMES).
  27. An increase in mitochondrial TOM activates apoptosis to drive retinal neurodegeneration.
  28. Importance of NAD+ Anabolism in Metabolic, Cardiovascular and Neurodegenerative Disorders.
  29. UQCRC2-related mitochondrial complex III deficiency, about 7 patients.
  30. Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin.
  31. How gene therapy is emerging from its 'dark age'.
  32. Mitochondrial Dysfunction in Down Syndrome: From Pathology to Therapy.
  33. Phosphorylation of the novel mTOR substrate Unkempt regulates cellular morphogenesis.
  34. Muscle PGC-1α modulates hepatic mitophagy regulation during aging.
  35. An atlas of late prenatal human neurodevelopment resolved by single-nucleus transcriptomics.
  1. J Pharmacol Exp Ther. 2022 Nov;383(2): 137-148
    Mitochondrial Dysfunction and Pharmacodynamics of Mitofusin Activation in Murine Charcot-Marie-Tooth Disease Type 2A.
    Antonietta Franco, Xiawei Dang, Lihong Zhang, Perry B Molinoff, Gerald W Dorn.
      Mitofusin (MFN) 1 and MFN2 are dynamin GTPase family mitochondrial proteins that mediate mitochondrial fusion requiring MFN conformational shifts, formation of macromolecular complexes on and between mitochondria, and GTP hydrolysis. Damaging MFN2 mutations cause an untreatable, largely pediatric progressive peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease type 2A. We used small molecule allosteric mitofusin activators that promote MFN conformations favoring fusion to interrogate the effects of MFN2 conformation and GTPase activity on MFN2-mediated mitochondrial fusion and motility in vitro. We translated these findings in vivo by defining dose-dependent pharmacodynamic and disease-modifying effects of mitofusin activators in murine CMT2A. MFN2 catalytic GTPase activity and MFN2 conformational switching are essential for mitochondrial fusion, but the two processes are separate and dissociable. We report the first concentration-response relationships for mitofusin activators to stimulate mitochondrial transport through CMT2A neuronal axons, which is similar to their stimulation of mitochondrial fusion. In CMT2A mice, intermittent (daily short acting) and sustained (twice daily long acting) mitofusin activation were equally effective in reversing neuromuscular degeneration. Moreover, acute dose-dependent pharmacodynamic effects of mitofusin activators on mitochondrial transport through CMT2A neuronal axons anticipated those for long-term reversal of neurodegenerative phenotypes. A crossover study showed that CMT2A neuronal deficits recurred after mitofusin activators are discontinued, and revealed that CMT2A can be ameliorated by mitofusin activation even in old (>74 week) mice. These data add to our understanding of mitochondrial dysfunction induced by a CMT2A MFN2 GTPase mutation and provide additional information supporting the approach of pharmacological mitofusin activation in CMT2A. SIGNIFICANCE: This study interrogated the roles of MFN2 catalytic activity and allosteric activation on impaired mitochondrial fusion and neuronal transport as they impact an untreatable peripheral neuropathy caused by MFN2 mutations, Charcot-Marie-Tooth disease type 2A. The results mechanistically link mitochondrial fusion and motility to the relaxed MFN2 protein conformation and correction of mitochondrial abnormalities to in vivo reversal of neurodegeneration in murine CMT2A.
    DOI:  https://doi.org/10.1124/jpet.122.001332
  2. Eur J Hum Genet. 2022 Dec 13.
    Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines.
    Eleni Mavraki, Robyn Labrum, Kate Sergeant, Charlotte L Alston, Cathy Woodward, Conrad Smith, Charlotte V Y Knowles, Yogen Patel, Philip Hodsdon, Jack P Baines, Emma L Blakely, James Polke, Robert W Taylor, Carl Fratter.
      Primary mitochondrial disease describes a diverse group of neuro-metabolic disorders characterised by impaired oxidative phosphorylation. Diagnosis is challenging; >350 genes, both nuclear and mitochondrial DNA (mtDNA) encoded, are known to cause mitochondrial disease, leading to all possible inheritance patterns and further complicated by heteroplasmy of the multicopy mitochondrial genome. Technological advances, particularly next-generation sequencing, have driven a shift in diagnostic practice from 'biopsy first' to genome-wide analyses of blood and/or urine DNA. This has led to the need for a reference framework for laboratories involved in mitochondrial genetic testing to facilitate a consistent high-quality service. In the United Kingdom, consensus guidelines have been prepared by a working group of Clinical Scientists from the NHS Highly Specialised Service followed by national laboratory consultation. These guidelines summarise current recommended technologies and methodologies for the analysis of mtDNA and nuclear-encoded genes in patients with suspected mitochondrial disease. Genetic testing strategies for diagnosis, family testing and reproductive options including prenatal diagnosis are outlined. Importantly, recommendations for the minimum levels of mtDNA testing for the most common referral reasons are included, as well as guidance on appropriate referrals and information on the minimal appropriate gene content of panels when analysing nuclear mitochondrial genes. Finally, variant interpretation and recommendations for reporting of results are discussed, focussing particularly on the challenges of interpreting and reporting mtDNA variants.
    DOI:  https://doi.org/10.1038/s41431-022-01249-w
  3. J Appl Physiol (1985). 2022 Dec 15.
    Exercise and mitochondrial remodeling to prevent age-related neurodegeneration.
    Colleen L O'Reilly, Benjamin F Miller, Tommy L Lewis.
      Healthy brain activity requires precise ion and energy management creating a strong reliance on mitochondrial function. Age-related neurodegeneration leads to a decline in mitochondrial function and increased oxidative stress, with associated declines in mitochondrial mass, respiration capacity, and respiration efficiency. The interdependent processes of mitochondrial protein turnover and mitochondrial dynamics, known together as mitochondrial remodeling, play essential roles in mitochondrial health and therefore brain function. This mini-review describes the role of mitochondria in neurodegeneration and brain health, current practices for assessing both aspects of mitochondrial remodeling, and how exercise mitigates the adverse effects of aging in the brain. Exercise training elicits functional adaptations to improve brain health, and current literature strongly suggests that mitochondrial remodeling plays a vital role in these positive adaptations. Despite substantial implications that the two aspects of mitochondrial remodeling are interdependent, very few investigations have simultaneously measured mitochondrial dynamics and protein synthesis. An improved understanding of the partnership between mitochondrial protein turnover and mitochondrial dynamics will provide a better understanding of their role in both brain health and disease, as well as how they induce protection following exercise.
    Keywords:  brain; exercise; mitochondria; mitochondria remodeling; neurodegeneration
    DOI:  https://doi.org/10.1152/japplphysiol.00611.2022
  4. BMJ Neurol Open. 2022 ;4(2): e000352
    Changing faces of mitochondrial disease: autosomal recessive POLG disease mimicking myasthenia gravis and progressive supranuclear palsy.
    Menatalla Elwan, Andrew M Schaefer, Kate Craig, Sila Hopton, Gavin Falkous, Emma L Blakely, Robert W Taylor, Naomi Warren.
       Background: Mitochondrial disorders are known to cause diverse neurological phenotypes which cause a diagnostic challenge to most neurologists. Pathogenic polymerase gamma (POLG) variants have been described as a cause of chronic progressive external ophthalmoplegia, which manifests with ptosis, horizontal and vertical eye movement restriction and myopathy. Autosomal dominant progressive external ophthalmoplegia is rarely associated with Parkinsonism responsive to levodopa.
    Methods: We report a case of a 58-year-old man who presented with an eye movement disorder then Parkinsonism who made his way through the myasthenia then the movement disorder clinic.
    Results: A diagnostic right tibialis anterior biopsy revealed classical hallmarks of mitochondrial disease, and genetic testing identified compound heterozygous pathogenic gene variants in the POLG gene. The patient was diagnosed with autosomal recessive POLG disease.
    Conclusions: It is important to maintain a high index of suspicion of pathogenic POLG variants in patients presenting with atypical Parkinsonism and ophthalmoplegia. Patients with POLG-related disease will usually have ptosis, and downgaze is typically preserved until late in the disease. Accurate diagnosis is essential for appropriate prognosis and genetic counselling.
    Keywords:  MITOCHONDRIAL DISORDERS; MYASTHENIA; SUPRANUCLEAR PALSY
    DOI:  https://doi.org/10.1136/bmjno-2022-000352
  5. Proc Natl Acad Sci U S A. 2022 Dec 20. 119(51): e2217949119
    An AAA-ATPase links mitochondrial division with DNA nucleoids.
    Nelson Yeung, Miho Iijima, Hiromi Sesaki.
      
    DOI:  https://doi.org/10.1073/pnas.2217949119
  6. Cureus. 2022 Nov;14(11): e31467
    Bilateral Nonsyndromic Sensorineural Hearing Loss Caused by a NARS2 Mutation.
    Fawzia Al-Sharif, Hussain Alsadeq, Aahid Rozan, Molham B Halabi, Hamzah Badwilan, Adel A Mohammed, Moshiur Rahman, Turki Balgith.
      Mitochondrial diseases disrupt the process of energy generation by the mitochondria, leading to manifestations that can affect almost any organ in the body. Although various possible clinical phenotypes can result, neurological and neuromuscular affection is most frequently encountered. NARS2 encodes an enzyme responsible for the conjugation of asparagine to its cognate mitochondrial transfer ribonucleic acid (tRNA) molecule, representing an essential step necessary for effective mitochondrial protein synthesis. As such, mutations in this gene can lead to poor mitochondrial gene expression and, consequently, poor energy output resulting in disease. Pathogenic variants in NARS2 have been known to cause neurodegenerative and myopathic syndromes in combined oxidative phosphorylation deficiency 24 (COXPD24). However, nonsyndromic autosomal recessive deafness 94 (DFNB94), with which only one family is known to be affected, has also been reported concerning NARS2. Our report demonstrates the association of a new pathogenic variant in mitochondrial asparaginyl-tRNA synthetase (NARS2) with nonsyndromic sensorineural hearing loss, thus confirming biallelic mutations in NARS2 as a cause of nonsyndromic deafness.
    Keywords:  aminoacyl-trna synthetase; hearing loss; mitochondrial disease; nars2; nonsyndromic deafness
    DOI:  https://doi.org/10.7759/cureus.31467
  7. Sci Rep. 2022 Dec 16. 12(1): 21725
    Investigating mitochondrial fission, fusion, and autophagy in retinal pigment epithelium from donors with age-related macular degeneration.
    Cody R Fisher, Adam A Shaaeli, Mara C Ebeling, Sandra R Montezuma, Deborah A Ferrington.
      Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries, characterized by the death of retinal pigment epithelial (RPE) cells and photoreceptors. Previous studies report an accumulation of damaged and dysfunctional mitochondria in RPE of human donors with AMD. Understanding how damaged mitochondria accumulate in AMD is an important step in discovering disease mechanisms and identifying therapeutic targets. In this report, we assessed mitochondrial fission and fusion by quantifying proteins and measured mitochondrial autophagy (mitophagy) via protein analysis and advanced imaging techniques using mitochondrial targeted mKeima in primary human RPE from donors with or without AMD. We report disease-specific differences in mitochondrial proteins that regulate fission, fusion, and mitophagy that were present at baseline and with treatments to stimulate these pathways. Data suggest AMD RPE utilize receptor-mediated mitophagy as a compensatory mechanism for deficits in the ubiquitin-mediated mitophagy pathway. These changes in mitochondrial homeostasis could lead to the buildup of damaged and dysfunctional mitochondria observed in the RPE of AMD donors.
    DOI:  https://doi.org/10.1038/s41598-022-26012-5
  8. J Cell Sci. 2022 Dec 01. pii: jcs259748. [Epub ahead of print]135(23):
    Diversity of mitophagy pathways at a glance.
    Ian G Ganley, Anne Simonsen.
      Mitochondria are crucial organelles that play a central role in various cell signaling and metabolic pathways. A healthy mitochondrial population is maintained through a series of quality control pathways and requires a fine-tuned balance between mitochondrial biogenesis and degradation. Defective targeting of dysfunctional mitochondria to lysosomes through mitophagy has been linked to several diseases, but the underlying mechanisms and the relative importance of distinct mitophagy pathways in vivo are largely unknown. In this Cell Science at a Glance and the accompanying poster, we describe our current understanding of how parts of, or whole, mitochondria are recognized by the autophagic machinery and targeted to lysosomes for degradation. We also discuss how this might be regulated under different physiological conditions to maintain mitochondrial and cellular health.
    Keywords:  BNIP3; HIF1; Mitochondria; Mitophagy; NIX; PINK1; Parkin; SLR; Selective autophagy
    DOI:  https://doi.org/10.1242/jcs.259748
  9. Methods Mol Biol. 2023 ;2609 227-249
    Methods to Assess the Role of PARPs in Regulating Mitochondrial Oxidative Function.
    Tünde Kovács, Boglárka Rauch, Edit Mikó, Péter Bai.
      PARP enzymes are involved in metabolic regulation and impact on a plethora of cellular metabolic pathways, among them, mitochondrial oxidative metabolism. The detrimental effects of PARP1 overactivation upon oxidative stress on mitochondrial oxidative metabolism was discovered in 1998. Since then, there was an enormous blooming in the understanding of the interplay between PARPs and mitochondria. Mitochondrial activity can be assessed by a comprehensive set of methods that we aim to introduce here.
    Keywords:  ARTD; Differentiation; Flow cytometry; Mitochondria; Mitochondrial fission; Mitochondrial fusion; Mitochondrial morphology; Oximetry; PARP; Seahorse extracellular flux analyzer; Substrate preference; Δψ
    DOI:  https://doi.org/10.1007/978-1-0716-2891-1_14
  10. Int J Mol Sci. 2022 Nov 25. pii: 14739. [Epub ahead of print]23(23):
    Nicotinamide Mononucleotide Supplementation Improves Mitochondrial Dysfunction and Rescues Cellular Senescence by NAD+/Sirt3 Pathway in Mesenchymal Stem Cells.
    Huan Wang, Yanan Sun, Chenchen Pi, Xiao Yu, Xingyu Gao, Chang Zhang, Hui Sun, Haiying Zhang, Yingai Shi, Xu He.
      In vitro expansion-mediated replicative senescence has severely limited the clinical applications of mesenchymal stem cells (MSCs). Accumulating studies manifested that nicotinamide adenine dinucleotide (NAD+) depletion is closely related to stem cell senescence and mitochondrial metabolism disorder. Promoting NAD+ level is considered as an effective way to delay aging. Previously, we have confirmed that nicotinamide mononucleotide (NMN), a precursor of NAD+, can alleviate NAD+ deficiency-induced MSC senescence. However, whether NMN can attenuate MSC senescence and its underlying mechanisms are still incompletely clear. The present study herein showed that late passage (LP) MSCs displayed lower NAD+ content, reduced Sirt3 expression and mitochondrial dysfunction. NMN supplementation leads to significant increase in intracellular NAD+ level, NAD+/ NADH ratio, Sirt3 expression, as well as ameliorated mitochondrial function and rescued senescent MSCs. Additionally, Sirt3 over-expression relieved mitochondrial dysfunction, and retrieved senescence-associated phenotypic features in LP MSCs. Conversely, inhibition of Sirt3 activity via a selective Sirt3 inhibitor 3-TYP in early passage (EP) MSCs resulted in aggravated cellular senescence and abnormal mitochondrial function. Furthermore, NMN administration also improves 3-TYP-induced disordered mitochondrial function and cellular senescence in EP MSCs. Collectively, NMN replenishment alleviates mitochondrial dysfunction and rescues MSC senescence through mediating NAD+/Sirt3 pathway, possibly providing a novel mechanism for MSC senescence and a promising strategy for anti-aging pharmaceuticals.
    Keywords:  MSC senescence; NAD+; NMN; Sirt3; mitochondrial function
    DOI:  https://doi.org/10.3390/ijms232314739
  11. Cells. 2022 Nov 24. pii: 3754. [Epub ahead of print]11(23):
    TFAM's Contributions to mtDNA Replication and OXPHOS Biogenesis Are Genetically Separable.
    Natalya Kozhukhar, Mikhail F Alexeyev.
      The ability of animal orthologs of human mitochondrial transcription factor A (hTFAM) to support the replication of human mitochondrial DNA (hmtDNA) does not follow a simple pattern of phylogenetic closeness or sequence similarity. In particular, TFAM from chickens (Gallus gallus, chTFAM), unlike TFAM from the "living fossil" fish coelacanth (Latimeria chalumnae), cannot support hmtDNA replication. Here, we implemented the recently developed GeneSwap approach for reverse genetic analysis of chTFAM to obtain insights into this apparent contradiction. By implementing limited "humanization" of chTFAM focused either on amino acid residues that make DNA contacts, or the ones with significant variances in side chains, we isolated two variants, Ch13 and Ch22. The former has a low mtDNA copy number (mtCN) but robust respiration. The converse is true of Ch22. Ch13 and Ch22 complement each other's deficiencies. Opposite directionalities of changes in mtCN and respiration were also observed in cells expressing frog TFAM. This led us to conclude that TFAM's contributions to mtDNA replication and respiratory chain biogenesis are genetically separable. We also present evidence that TFAM residues that make DNA contacts play the leading role in mtDNA replication. Finally, we present evidence for a novel mode of regulation of the respiratory chain biogenesis by regulating the supply of rRNA subunits.
    Keywords:  GeneSwap approach; TFAM; mtDNA instability; mtDNA replication; mtDNA transcription
    DOI:  https://doi.org/10.3390/cells11233754
  12. J Inherit Metab Dis. 2022 Dec 11.
    Transcriptomic analyses reveal neuronal specificity of Leigh syndrome associated genes.
    Azizia Wahedi, Chandika Soondram, Alan E Murphy, Nathan Skene, Shamima Rahman.
      Leigh syndrome is a rare inherited, complex, neurometabolic disorder with genetic and clinical heterogeneity. Features present in affected patients range from classical stepwise developmental regression to ataxia, seizures, tremor, and occasionally psychiatric manifestations. Currently, more than 100 monogenic causes of Leigh syndrome have been identified, yet, the pathophysiology remains unknown. Here, we sought to determine the cellular specificity within the brain of all genes currently associated with Leigh syndrome. Further, we aimed to investigate potential genetic commonalities between Leigh syndrome and other disorders with overlapping clinical features. Enrichment of our target genes within the brain was evaluated with co-expression (CoExp) network analyses constructed using existing UK Brain Expression Consortium data. To determine the cellular specificity of the Leigh associated genes, we employed expression weighted cell type enrichment (EWCE) analysis of single cell RNA-Seq data. Finally, CoExp network modules demonstrating enrichment of Leigh syndrome associated genes were then utilised for synaptic gene ontology analysis and heritability analysis. CoExp network analyses revealed that Leigh syndrome associated genes exhibit the highest levels of expression in brain regions most affected on MRI in affected patients. EWCE revealed significant enrichment of target genes in hippocampal and somatosensory pyramidal neurons and interneurons of the brain. Analysis of CoExp modules enriched with our target genes revealed preferential association with pre-synaptic structures. Heritability studies suggested some common enrichment between Leigh syndrome and Parkinson disease and epilepsy. Our findings suggest a primary mitochondrial dysfunction as the underlying basis of Leigh syndrome with associated genes primarily expressed in neuronal cells. This article is protected by copyright. All rights reserved.
    Keywords:  CoExp network; EWCE; Leigh syndrome spectrum; Primary mitochondrial disease; transcriptomics
    DOI:  https://doi.org/10.1002/jimd.12578
  13. Int J Mol Sci. 2022 Dec 02. pii: 15197. [Epub ahead of print]23(23):
    Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments.
    Artem P Gureev, Victoria G Khorolskaya, Irina S Sadovnikova, Ekaterina A Shaforostova, Vadim R Cherednichenko, Inna Y Burakova, Egor Y Plotnikov, Vasily N Popov.
      In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test. Cognitive impairments in 15-month-old mice correlated with a decrease in Bdnf expression in the hippocampus, Nfe2l2 expression, and an increase in the number of mtDNA damage in the cerebral cortex. Thus, these signaling pathways may be perspective targets for pharmacological intervention to maintain mitochondrial quality control, neuronal plasticity, and prevent the development of age-related cognitive impairment.
    Keywords:  Morris water maze; aging; brain-derived neurotrophic factor; cognitive deficit; mammalian target of rapamycin complex 1; mitochondrial DNA damage; nuclear erythroid 2-related factor 2
    DOI:  https://doi.org/10.3390/ijms232315197
  14. Am J Ophthalmol. 2022 Dec 07. pii: S0002-9394(22)00464-0. [Epub ahead of print]
    Safety of lenadogene nolparvovec gene therapy over 5 years in 189 patients with Leber hereditary optic neuropathy.
    LHON Study Group
       PURPOSE: Evaluate the safety profile of lenadogene nolparvovec (Lumevoq®) in patients with Leber hereditary optic neuropathy.
    DESIGN: Pooled analysis of safety data from 5 clinical studies.
    METHODS: A total of 189 patients received single unilateral or bilateral intravitreal injections of a recombinant adeno-associated virus 2 (rAAV2/2) vector encoding the human wild-type ND4 gene. Adverse events (AEs) were collected throughout the studies, up to 5 years. Intraocular inflammation and increased intraocular pressure (IOP) were ocular AEs of special interest. Other assessments included ocular examinations, vector bio-dissemination and systemic immune responses against rAAV2/2.
    RESULTS: Almost all patients (95.2%) received 9 × 1010 viral genomes and 87.8% had at least 2 years of follow-up. Most patients (75.1%) experienced at least one systemic AE, but systemic treatment-related AEs occurred in 3 patients, none was serious. Intraocular inflammation was reported in 75.6% of lenadogene nolparvovec-treated eyes. Almost all intraocular inflammations occurred in the anterior chamber (58.8%) or in the vitreous (40.3%) and was of mild (90.3%) or moderate (8.8%) intensity; most resolved with topical corticosteroids alone. All IOP increases were mild to moderate in intensity. No AE led to study discontinuation. Bio-dissemination of lenadogene nolparvovec and systemic immune response were limited. The safety profile was comparable for patients treated bilaterally and unilaterally.
    CONCLUSIONS: Lenadogene nolparvovec has a good overall safety profile with excellent systemic tolerability, consistent with limited bio-dissemination. The product is well tolerated, with mostly mild ocular side effects responsive to conventional ophthalmologic treatments.
    Keywords:  Leber hereditary optic neuropathy; intravitreal gene therapy; safety
    DOI:  https://doi.org/10.1016/j.ajo.2022.11.026
  15. Nat Rev Endocrinol. 2022 Dec 14.
    A mitochondrial trigger for beige adipocyte development.
    Shimona Starling.
      
    DOI:  https://doi.org/10.1038/s41574-022-00792-2
  16. Neuroimage Clin. 2022 ;pii: S2213-1582(22)00305-9. [Epub ahead of print]36 103240
    Neuroimaging in Leber Hereditary Optic Neuropathy: State-of-the-art and future prospects.
    Hugo T Chow-Wing-Bom, Martina F Callaghan, Junqing Wang, Shihui Wei, Frederic Dick, Patrick Yu-Wai-Man, Tessa M Dekker.
      Leber Hereditary Optic Neuropathy (LHON) is an inherited mitochondrial retinal disease that causes the degeneration of retinal ganglion cells and leads to drastic loss of visual function. In the last decades, there has been a growing interest in using Magnetic Resonance Imaging (MRI) to better understand mechanisms of LHON beyond the retina. This is partially due to the emergence of gene-therapies for retinal diseases, and the accompanying expanded need for reliably quantifying and monitoring visual processing and treatment efficiency in patient populations. This paper aims to draw a current picture of key findings in this field so far, the challenges of using neuroimaging methods in patients with LHON, and important open questions that MRI can help address about LHON disease mechanisms and prognoses, including how downstream visual brain regions are affected by the disease and treatment and why, and how scope for neural plasticity in these pathways may limit or facilitate recovery.
    Keywords:  DTI; LHON; MRI; Optic neuropathies; Optic pathways
    DOI:  https://doi.org/10.1016/j.nicl.2022.103240
  17. Trends Pharmacol Sci. 2022 Dec 07. pii: S0165-6147(22)00254-1. [Epub ahead of print]
    Mitochondrial dynamics proteins as emerging drug targets.
    Emmanouil Zacharioudakis, Evripidis Gavathiotis.
      The importance of mitochondrial dynamics, the physiological process of mitochondrial fusion and fission, in regulating diverse cellular functions and cellular fitness has been well established. Several pathologies are associated with aberrant mitochondrial fusion or fission that is often a consequence of deregulated mitochondrial dynamics proteins; however, pharmacological targeting of these proteins has been lacking and is challenged by complex molecular mechanisms. Recent studies have advanced our understanding in this area and have enabled rational drug design and chemical screening strategies. We provide an updated overview of the regulatory mechanisms of fusion and fission proteins, their structure-function relationships, and the discovery of pharmacological modulators demonstrating their therapeutic potential. These advances provide exciting opportunities for the development of prototype therapeutics for various diseases.
    Keywords:  activators; fission; fusion; inhibitors; mitochondria; mitochondrial dynamics; mitochondrial structure
    DOI:  https://doi.org/10.1016/j.tips.2022.11.004
  18. Ageing Res Rev. 2022 Dec 09. pii: S1568-1637(22)00259-8. [Epub ahead of print]84 101817
    PINK1/Parkin-mediated mitophagy in neurodegenerative diseases.
    Jie Li, Dongming Yang, Zhiping Li, Mengyang Zhao, Dongdong Wang, Zhixin Sun, Pei Wen, Yuexin Dai, Fengting Gou, Yilan Ji, Deming Zhao, Lifeng Yang.
      Mitochondria play key roles in bioenergetics, metabolism, and signaling; therefore, stable mitochondrial function is essential for cell survival, particularly in energy-intensive neuronal cells. In neurodegenerative diseases, damaged mitochondria accumulate in neurons causing associated bioenergetics deficiency, impaired cell signaling, defective cytoplasmic calcium buffering, and other pathological changes. Mitochondrial quality control is an important mechanism to ensure the maintenance of mitochondrial health, homeostasis, and mitophagy, the latter of which is a pathway that delivers defective mitochondria to the lysosome for degradation. Defective mitophagy is thought to be responsible for the accumulation of damaged mitochondria, which leads to cellular dysfunction and/or death in neurodegenerative diseases. PINK1/Parkin mainly regulates ubiquitin-dependent mitophagy, which is crucial for many aspects of mitochondrial physiology, particularly the initiation of autophagic mechanisms. Therefore, in the present review, we summarize the current knowledge of the conventional mitophagy pathway, focusing on the molecular mechanisms underlying mitophagy dysregulation in prion disease and other age-related neurodegenerative diseases, especially in relation to the PINK1/Parkin pathway. Moreover, we list the inducers of mitophagy that possess neuroprotective effects, in addition to their mechanisms related to the PINK1/Parkin pathway. These mechanisms may provide potential interventions centered on the regulation of mitophagy and offer therapeutic strategies for the treatment of neurodegenerative diseases.
    Keywords:  Mitochondria; Mitochondrial quality control; Mitophagy; Neurodegenerative diseases; PINK1/Parkin
    DOI:  https://doi.org/10.1016/j.arr.2022.101817
  19. Mitochondrion. 2022 Dec 10. pii: S1567-7249(22)00106-4. [Epub ahead of print]68 105-113
    Paternal aging impacts mitochondrial DNA content and telomere length in mouse embryos.
    Jun Ito, Mio Kageyama, Shunsuke Hara, Takuya Sato, Koumei Shirasuna, Hisataka Iwata.
      Mitochondrial DNA (mtDNA) copy number and telomere length (TL) in blastocysts derived from the same male mice at young (10-19-week-old) and aged (40-49-week-old) time points and mtDNA and TL in the hearts of offspring derived from young and aged male mice were examined. Paternal aging correlated with reduced mtDNA and TL in blastocysts. mtDNA and TL were significantly correlated, which was also observed in bovine blastocysts. Moreover, mtDNA in the heart of offspring was reduced in male mice with paternal aging. In conclusion, paternal aging affects embryonic mtDNA and TL, potentially impacting their offspring.
    Keywords:  Mitochondrial DNA; Mouse embryos; Paternal aging; Telomere length
    DOI:  https://doi.org/10.1016/j.mito.2022.12.002
  20. EMBO J. 2022 Dec 14. e111372
    NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy.
    Tetsushi Kataura, Elsje G Otten, Yoana Rabanal-Ruiz, Elias Adriaenssens, Francesca Urselli, Filippo Scialo, Lanyu Fan, Graham R Smith, William M Dawson, Xingxiang Chen, Wyatt W Yue, Agnieszka K Bronowska, Bernadette Carroll, Sascha Martens, Michael Lazarou, Viktor I Korolchuk.
      Mitophagy, the elimination of mitochondria via the autophagy-lysosome pathway, is essential for the maintenance of cellular homeostasis. The best characterised mitophagy pathway is mediated by stabilisation of the protein kinase PINK1 and recruitment of the ubiquitin ligase Parkin to damaged mitochondria. Ubiquitinated mitochondrial surface proteins are recognised by autophagy receptors including NDP52 which initiate the formation of an autophagic vesicle around the mitochondria. Damaged mitochondria also generate reactive oxygen species (ROS) which have been proposed to act as a signal for mitophagy, however the mechanism of ROS sensing is unknown. Here we found that oxidation of NDP52 is essential for the efficient PINK1/Parkin-dependent mitophagy. We identified redox-sensitive cysteine residues involved in disulphide bond formation and oligomerisation of NDP52 on damaged mitochondria. Oligomerisation of NDP52 facilitates the recruitment of autophagy machinery for rapid mitochondrial degradation. We propose that redox sensing by NDP52 allows mitophagy to function as a mechanism of oxidative stress response.
    Keywords:  NDP52; autophagy; mitophagy; p62; redox
    DOI:  https://doi.org/10.15252/embj.2022111372
  21. Front Genet. 2022 ;13 1004598
    Clinical heterogeneity of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome in thirteen palestinian patients and report of a novel variant in the SLC25A15 gene.
    Imad Dweikat, Reham Khalaf-Nazzal.
      Background: Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome, is a rare autosomal recessive disorder characterized by impaired ornithine transport across the inner mitochondrial membrane. HHH is caused by biallelic disease-causing variants in the SLC25A15 gene. The clinical presentation of HHH is highly variable ranging from severe neonatal encephalopathy and hepatic failure to a milder form with corresponding learning difficulties. Methods: In this study, data from thirteen patients with HHH syndrome, diagnosed between the age of 1 week-29 years at two tertiary care centers in Palestine, is presented. The clinical, biochemical, and molecular data are reviewed. Results: Analysis of the SLC25A15 gene sequence revealed a novel homozygous frameshift deletion in exon 5, NM_014252.4:c.552-555delTTTC; p (Phe185SerfsTer8) in nine patients. The remaining four patients had a recurrent homozygous frameshift variant; NM_014252.4:c.446delG, (p.Ser149ThrfsTer45). The major acute clinical presentation found was encephalopathy and liver dysfunction. Nervous system involvement was common, progressive, and presented with signs of upper motor neuron disease as well as variable degrees of cognitive impairment. One patient had an initial presentation in adulthood with acute encephalopathy that responded well to treatment. There was no clear genotype-phenotype correlation. Conclusion: Our results confirm the marked clinical heterogeneity of HHH including severe neonatal presentation, hepatic failure, and progressive pyramidal tract dysfunction in all age groups. The disease progression was variable, even in patients with the same genetic variant, and in patients with severe neonatal-onset hepatic encephalopathy. We report a novel pathogenic variant in the SLC25A15 gene, further expanding the molecular spectrum of the disease.
    Keywords:  SLC25A15 gene; autosomal recessive; frameshift variant; hepatic failure; homocitrullinuria; hyperammonemia; hyperornithinemia; spasticity
    DOI:  https://doi.org/10.3389/fgene.2022.1004598
  22. Int J Mol Sci. 2022 Nov 25. pii: 14741. [Epub ahead of print]23(23):
    Targeting Mitochondrial Dynamics Proteins for the Development of Therapies for Cardiovascular Diseases.
    Alexander V Blagov, Sergey Kozlov, Tatiana Blokhina, Vasily N Sukhorukov, Aleksander N Orekhov.
      Cardiovascular diseases are one of the leading causes of death worldwide. The identification of new pathogenetic targets contributes to more efficient development of new types of drugs for the treatment of cardiovascular diseases. This review highlights the problem of mitochondrial dynamics disorders, in the context of cardiovascular diseases. A change in the normal function of mitochondrial dynamics proteins is one of the reasons for the development of the pathological state of cardiomyocytes. Based on this, therapeutic targeting of these proteins may be a promising strategy in the development of cardiac drugs. Here we will consider changes for each process of mitochondrial dynamics in cardiovascular diseases: fission and fusion of mitochondria, mitophagy, mitochondrial transport and biogenesis, and also analyze the prospects of the considered protein targets based on existing drug developments.
    Keywords:  cardiovascular disease; mitochondria; mitochondrial dynamic
    DOI:  https://doi.org/10.3390/ijms232314741
  23. Environ Sci Technol. 2022 Dec 14.
    In Utero Exposure to Air Pollutants and Mitochondrial Heteroplasmy in Neonates.
    Charlotte Cosemans, Congrong Wang, Dries S Martens, Bram G Janssen, Charlotte Vanpoucke, Wouter Lefebvre, Karen Smeets, Tim S Nawrot, Michelle Plusquin.
      Mitochondria are sensitive to oxidative stress, which can be caused by traffic-related air pollution. Placental mitochondrial DNA (mtDNA) mutations have been previously linked with air pollution. However, the relationship between prenatal air pollution and cord-blood mtDNA mutations has been poorly understood. Therefore, we hypothesized that prenatal particulate matter (PM2.5) and NO2 exposures are associated with cord-blood mtDNA heteroplasmy. As part of the ENVIRONAGE cohort, 200 mother-newborn pairs were recruited. Cord-blood mitochondrial single-nucleotide polymorphisms were identified by whole mitochondrial genome sequencing, and heteroplasmy levels were evaluated based on the variant allele frequency (VAF). Outdoor PM2.5 and NO2 concentrations were determined by a high-resolution spatial-temporal interpolation method based on the maternal residential address. Distributed lag linear models were used to determine sensitive time windows for the association between NO2 exposure and cord-blood mtDNA heteroplasmy. A 5 μg/m3 increment in NO2 was linked with MT-D-Loop16311T>C heteroplasmy from gestational weeks 17-25. MT-CYTB14766C>T was negatively associated with NO2 exposure in mid pregnancy, from weeks 14-17, and positively associated in late pregnancy, from weeks 31-36. No significant associations were observed with prenatal PM2.5 exposure. This is the first study to show that prenatal NO2 exposure is associated with cord-blood mitochondrial mutations and suggests two critical windows of exposure in mid-to-late pregnancy.
    Keywords:  DLM; SNP; air pollution; heteroplasmy; mitochondria
    DOI:  https://doi.org/10.1021/acs.est.2c02556
  24. Nat Commun. 2022 Dec 13. 13(1): 7732
    CENP-F-dependent DRP1 function regulates APC/C activity during oocyte meiosis I.
    Cheng-Jie Zhou, Xing-Yue Wang, Yan-Hua Dong, Dong-Hui Wang, Zhe Han, Xiao-Jie Zhang, Qing-Yuan Sun, John Carroll, Cheng-Guang Liang.
      Chromosome segregation is initiated by cohesin degradation, which is driven by anaphase-promoting complex/cyclosome (APC/C). Chromosome cohesin is removed by activated separase, with the degradation of securin and cyclinB1. Dynamin-related protein 1 (DRP1), a component of the mitochondrial fission machinery, is related to cyclin dynamics in mitosis progression. Here, we show that DRP1 is recruited to the kinetochore by centromeric Centromere protein F (CENP-F) after nuclear envelope breakdown in mouse oocytes. Loss of DRP1 during prometaphase leads to premature cohesin degradation and chromosome segregation. Importantly, acute DRP1 depletion activates separase by initiating cyclinB1 and securin degradation during the metaphase-to-anaphase transition. Finally, we demonstrate that DRP1 is bound to APC2 to restrain the E3 ligase activity of APC/C. In conclusion, DRP1 is a CENP-F-dependent atypical spindle assembly checkpoint (SAC) protein that modulates metaphase-to-anaphase transition by controlling APC/C activity during meiosis I in oocytes.
    DOI:  https://doi.org/10.1038/s41467-022-35461-5
  25. Int J Mol Sci. 2022 Dec 05. pii: 15354. [Epub ahead of print]23(23):
    Super-Resolution Microscopy to Study Interorganelle Contact Sites.
    Jon Ander Nieto-Garai, June Olazar-Intxausti, Itxaso Anso, Maier Lorizate, Oihana Terrones, Francesc-Xabier Contreras.
      Interorganelle membrane contact sites (MCS) are areas of close vicinity between the membranes of two organelles that are maintained by protein tethers. Recently, a significant research effort has been made to study MCS, as they are implicated in a wide range of biological functions, such as organelle biogenesis and division, apoptosis, autophagy, and ion and phospholipid homeostasis. Their composition, characteristics, and dynamics can be studied by different techniques, but in recent years super-resolution fluorescence microscopy (SRFM) has emerged as a powerful tool for studying MCS. In this review, we first explore the main characteristics and biological functions of MCS and summarize the different approaches for studying them. Then, we center on SRFM techniques that have been used to study MCS. For each of the approaches, we summarize their working principle, discuss their advantages and limitations, and explore the main discoveries they have uncovered in the field of MCS.
    Keywords:  PALM; SIM; SMLM; STED; STORM; TIRFM; membrane contact sites; organelles; super-resolution microscopy
    DOI:  https://doi.org/10.3390/ijms232315354
  26. Neurol Genet. 2022 Dec;8(6): e200034
    Efficacy and Safety of Leriglitazone in Patients With Friedreich Ataxia: A Phase 2 Double-Blind, Randomized Controlled Trial (FRAMES).
    Massimo Pandolfo, Kathrin Reetz, Alejandra Darling, Francisco Javier Rodriguez de Rivera, Pierre-Gilles Henry, James Joers, Christophe Lenglet, Isaac Adanyeguh, Dinesh Deelchand, Fanny Mochel, Françoise Pousset, Sílvia Pascual, Delphine Van den Eede, Itziar Martin-Ugarte, Anna Vilà-Brau, Adriana Mantilla, María Pascual, Marc Martinell, Uwe Meya, Alexandra Durr.
       Background and Objectives: Friedreich ataxia (FRDA) is an autosomal recessive ataxia with no approved treatments. Leriglitazone is a selective peroxisome proliferator-activated receptor γ agonist that crosses the blood-brain barrier and, in preclinical models, improved mitochondrial function and energy production. We assessed effects of leriglitazone in patients with FRDA in a proof-of-concept study.
    Methods: In this double-blind, randomized controlled trial, eligible participants (age 12-60 years) had genetically confirmed FRDA, a Scale for the Assessment and Rating of Ataxia (SARA) total score <25, and a SARA item 1 score of 2-6, inclusive. Key exclusion criteria were age at FRDA onset ≥25 years and history of cardiac dysfunction. Participants were randomly assigned (2:1) to receive a daily, oral, individualized dose of leriglitazone or placebo for 48 weeks. The primary endpoint was the change from baseline to week 48 in spinal cord area (C2-C3) (measured by MRI). Secondary endpoints included the change from baseline to week 48 in iron accumulation in the dentate nucleus (quantitative susceptibility mapping) and total N-acetylaspartate to myo-inositol (tNAA/mIns) ratio.
    Results: Overall, 39 patients were enrolled (mean age 24 years; 43.6% women; mean time since symptom onset 10.5 years): 26 patients received leriglitazone (20 completed) and 13 received placebo (12 completed). There was no difference between groups in spinal cord area from baseline to week 48 (least-squares [LS] mean change [standard error (SE)]: leriglitazone, -0.39 [0.55] mm2; placebo, 0.08 [0.72] mm2; p = 0.61). Iron accumulation in the dentate nucleus was greater with placebo (LS mean change [SE]: leriglitazone, 0.10 [1.33] ppb; placebo, 4.86 [1.84] ppb; p = 0.05), and a numerical difference was seen in tNAA/mIns ratio (LS mean change [SE]: leriglitazone, 0.03 [0.02]; placebo, -0.02 [0.03]; p = 0.25). The most frequent adverse event was peripheral edema (leriglitazone 73.1%, placebo 0%).
    Discussion: The primary endpoint of change in spinal cord area was not met. Secondary endpoints provide evidence supporting proof of concept for leriglitazone mode of action and, with acceptable safety data, support larger studies in patients with FRDA.
    Trial Registration Information: ClinicalTrials.gov: NCT03917225; EudraCT: 2018-004405-64; submitted April 17, 2019; first patient enrolled April 2, 2019. clinicaltrials.gov/ct2/show/NCT03917225?term=NCT03917225&draw=2&rank=1.
    Classification of Evidence: This study provides Class I evidence that individualized dosing of leriglitazone, compared with placebo, is not associated with changes in spinal cord area in patients with FRDA.
    DOI:  https://doi.org/10.1212/NXG.0000000000200034
  27. Sci Rep. 2022 Dec 14. 12(1): 21634
    An increase in mitochondrial TOM activates apoptosis to drive retinal neurodegeneration.
    Agalya Periasamy, Naomi Mitchell, Olga Zaytseva, Arjun S Chahal, Jiamin Zhao, Peter M Colman, Leonie M Quinn, Jacqueline M Gulbis.
      Intronic polymorphic TOMM40 variants increasing TOMM40 mRNA expression are strongly correlated to late onset Alzheimer's Disease. The gene product, hTomm40, encoded in the APOE gene cluster, is a core component of TOM, the translocase that imports nascent proteins across the mitochondrial outer membrane. We used Drosophila melanogaster eyes as an in vivo model to investigate the relationship between elevated Tom40 (the Drosophila homologue of hTomm40) expression and neurodegeneration. Here we provide evidence that an overabundance of Tom40 in mitochondria invokes caspase-dependent cell death in a dose-dependent manner, leading to degeneration of the primarily neuronal eye tissue. Degeneration is contingent on the availability of co-assembling TOM components, indicating that an increase in assembled TOM is the factor that triggers apoptosis and degeneration in a neural setting. Eye death is not contingent on inner membrane translocase components, suggesting it is unlikely to be a direct consequence of impaired import. Another effect of heightened Tom40 expression is upregulation and co-association of a mitochondrial oxidative stress biomarker, DmHsp22, implicated in extension of lifespan, providing new insight into the balance between cell survival and death. Activation of regulated death pathways, culminating in eye degeneration, suggests a possible causal route from TOMM40 polymorphisms to neurodegenerative disease.
    DOI:  https://doi.org/10.1038/s41598-022-23280-z
  28. Drugs Aging. 2022 Dec 13.
    Importance of NAD+ Anabolism in Metabolic, Cardiovascular and Neurodegenerative Disorders.
    Tessa Helman, Nady Braidy.
      The role of nicotinamide adenine dinucleotide (NAD+) in ageing has emerged as a critical factor in understanding links to a wide range of chronic diseases. Depletion of NAD+, a central redox cofactor and substrate of numerous metabolic enzymes, has been detected in many major age-related diseases. However, the mechanisms behind age-associated NAD+ decline remains poorly understood. Despite limited conclusive evidence, supplements aimed at increasing NAD+ levels are becoming increasingly popular. This review provides renewed insights regarding the clinical utility and benefits of NAD+ precursors, namely nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), in attenuating NAD+ decline and phenotypic characterization of age-related disorders, including metabolic, cardiovascular and neurodegenerative diseases. While it is anticipated that NAD+ precursors can play beneficial protective roles in several conditions, they vary in their ability to promote NAD+ anabolism with differing adverse effects. Careful evaluation of the role of NAD+, whether friend or foe in ageing, should be considered.
    DOI:  https://doi.org/10.1007/s40266-022-00989-0
  29. Mitochondrion. 2022 Dec 09. pii: S1567-7249(22)00105-2. [Epub ahead of print]
    UQCRC2-related mitochondrial complex III deficiency, about 7 patients.
    Bansept Claire, Gaignard Pauline, Lebigot Elise, Eyer Didier, Delplancq Geoffroy, Hoebeke Célia, Mazodier Karin, Ledoyen Anaïs, Rouzier Cécile, Fragaki Konstantina, Ait-El-Mkadem Saadi Samira, Philippe Christophe, Bruel Ange-Line Christophe, Faivre Laurence, Feillet François, Abi Warde Marie-Thérèse.
      Isolated complex III defect is a relatively rare cause of mitochondrial disorder. New genes involved were identified in the last two decades, with only a few cases described for each deficiency. UQCRC2, which encodes ubiquinol-cytochrome c reductase core protein 2, is one of the eleven structural subunits of complex III. We report seven French patients with UQCRC2 deficiency to complete the phenotype reported so far. We highlight the similarities with neoglucogenesis defect during decompensations - hypoglycaemias, liver failure and lactic acidosis - and point out the rapid improvement with glucose fluid infusion, which is a remarkable feature for a mitochondrial disorder. Finally, we discuss the relevance of coenzyme Q10 supplementation in this defect.
    Keywords:  UQCRC2; coenzyme Q10; complex III deficiency; hypoglycaemia; liver failure
    DOI:  https://doi.org/10.1016/j.mito.2022.12.001
  30. Aging Cell. 2022 Dec 14. e13754
    Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin.
    Michael Vreones, Maja Mustapic, Ruin Moaddel, Krishna A Pucha, Jacqueline Lovett, Douglas R Seals, Dimitrios Kapogiannis, Christopher R Martens.
      Declining nicotinamide adenine dinucleotide (NAD+ ) concentration in the brain during aging contributes to metabolic and cellular dysfunction and is implicated in the pathogenesis of aging-associated neurological disorders. Experimental therapies aimed at boosting brain NAD+ levels normalize several neurodegenerative phenotypes in animal models, motivating their clinical translation. Dietary intake of NAD+ precursors, such as nicotinamide riboside (NR), is a safe and effective avenue for augmenting NAD+ levels in peripheral tissues in humans, yet evidence supporting their ability to raise NAD+ levels in the brain or engage neurodegenerative disease pathways is lacking. Here, we studied biomarkers in plasma extracellular vesicles enriched for neuronal origin (NEVs) from 22 healthy older adults who participated in a randomized, placebo-controlled crossover trial (NCT02921659) of oral NR supplementation (500 mg, 2x /day, 6 weeks). We demonstrate that oral NR supplementation increases NAD+ levels in NEVs and decreases NEV levels of Aβ42, pJNK, and pERK1/2 (kinases involved in insulin resistance and neuroinflammatory pathways). In addition, changes in NAD(H) correlated with changes in canonical insulin-Akt signaling proteins and changes in pERK1/2 and pJNK. These findings support the ability of orally administered NR to augment neuronal NAD+ levels and modify biomarkers related to neurodegenerative pathology in humans. Furthermore, NEVs offer a new blood-based window into monitoring the physiologic response of NR in the brain.
    Keywords:  NAD+; NADH; extracellular vesicles; neurodegenerative disease
    DOI:  https://doi.org/10.1111/acel.13754
  31. Nature. 2022 Dec;612(7940): S24-S26
    How gene therapy is emerging from its 'dark age'.
    Gemma Conroy.
      
    Keywords:  Diseases; Drug discovery; Gene therapy
    DOI:  https://doi.org/10.1038/d41586-022-04210-5
  32. Neuroscience. 2022 Dec 07. pii: S0306-4522(22)00603-0. [Epub ahead of print]
    Mitochondrial Dysfunction in Down Syndrome: From Pathology to Therapy.
    Kai-Leng Tan, Han-Chung Lee, Pike-See Cheah, King-Hwa Ling.
      Mitochondrial dysfunctions have been described in Down syndrome (DS) caused by either partial or full trisomy of chromosome 21 (HSA21). Mitochondria play a crucial role in various vital functions in eukaryotic cells, especially in energy production, calcium homeostasis and programmed cell death. The function of mitochondria is primarily regulated by genes encoded in the mitochondrion and nucleus. Many genes on HSA21 are involved in oxidative phosphorylation (OXPHOS) and regulation of mitochondrial functions. This review highlights the HSA21 dosage-sensitive nuclear-encoded mitochondrial genes associated with overexpression-related phenotypes seen in DS. This includes impaired mitochondrial dynamics, structural defects and dysregulated bioenergetic profiles such as OXPHOS deficiency and reduced ATP production. Various therapeutic approaches for modulating energy deficits in DS, effects and molecular mechanism of gene therapy and drugs that exert protective effects through modulation of mitochondrial function and attenuation of oxidative stress in DS cells were discussed. It is prudent that improving DS pathophysiological conditions or quality of life may be feasible by targeting something as simple as cellular mitochondria biogenesis and function.
    Keywords:  Down syndrome; anaerobic glucose metabolism; energy metabolism; mitochondrial dysfunction; oxidative; phosphorylation; triomy 21
    DOI:  https://doi.org/10.1016/j.neuroscience.2022.12.003
  33. J Biol Chem. 2022 Dec 09. pii: S0021-9258(22)01231-5. [Epub ahead of print] 102788
    Phosphorylation of the novel mTOR substrate Unkempt regulates cellular morphogenesis.
    Pranetha Baskaran, Simeon R Mihaylov, Elin Vinsland, Kriti Shah, Lucy Granat, Sila K Ultanir, Andrew R Tee, Jernej Murn, Joseph M Bateman.
      Mechanistic target of rapamycin (mTOR) is a protein kinase that integrates multiple inputs to regulate anabolic cellular processes. For example , mTOR complex I (mTORC1) has key functions in growth control, autophagy and metabolism. However, much less is known about the signaling components that act downstream of mTORC1 to regulate cellular morphogenesis. Here we show that the RNA-binding protein Unkempt, a key regulator of cellular morphogenesis, is a novel substrate of mTORC1. We show that Unkempt phosphorylation is regulated by nutrient levels and growth factors via mTORC1. To analyze Unkempt phosphorylation, we immunoprecipitated Unkempt from cells in the presence or absence of the mTORC1 inhibitor rapamycin and used mass spectrometry to identify mTORC1-dependent phosphorylated residues. This analysis showed that mTORC1-dependent phosphorylation is concentrated in a serine-rich intrinsically disordered region in the C-terminal half of Unkempt. We also found that Unkempt physically interacts with and is directly phosphorylated by mTORC1 through binding to the regulatory-associated protein of mTOR, Raptor. Furthermore, analysis in the developing brain of mice lacking TSC1 expression showed that phosphorylation of Unkempt is mTORC1-dependent in vivo. Finally, mutation analysis of key serine/threonine residues in the serine-rich region indicates that phosphorylation inhibits the ability of Unkempt to induce a bipolar morphology. Phosphorylation within this serine-rich region thus profoundly affects the ability of Unkempt to regulate cellular morphogenesis. Taken together, our findings reveal a novel molecular link between mTORC1 signaling and cellular morphogenesis.
    Keywords:  Raptor; Unkempt; cellular morphogenesis; intrinsically disordered region; mTOR; phosphorylation
    DOI:  https://doi.org/10.1016/j.jbc.2022.102788
  34. Exp Gerontol. 2022 Dec 12. pii: S0531-5565(22)00355-2. [Epub ahead of print] 112046
    Muscle PGC-1α modulates hepatic mitophagy regulation during aging.
    Natascha Masselkhi Christensen, Stine Ringholm, Bjørg Thiellesen Buch, Anders Gudiksen, Jens Frey Halling, Henriette Pilegaard.
      Aging has been suggested to be associated with changes in oxidative capacity, autophagy, and mitophagy in the liver, but a simultaneous evaluation of these key cellular processes is lacking. Moreover, skeletal muscle Transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator(PGC)-1α has been reported to mediate inter-organ signaling through myokines with regulatory effects in the liver, but the potential role of muscle PGC-1α on hepatic changes with age remains to be resolved. The aim of the present study was therefore to investigate 1) the effect of aging on mitochondrial autophagy and mitophagy capacity in mouse liver and 2) whether muscle PGC-1α is required for maintaining autophagy and mitophagy capacity in the liver during aging. The liver was obtained from young (Young) and aged (Aged) inducible muscle-specific PGC-1α knockout (iMKO) and floxed littermate control mice. Aging increased liver p62, Parkin and Protein-interacting protein(BNIP)3 protein with no effect of muscle specific PGC-1α knockout, while liver Microtubule-associated protein 1A/1B-light chain 3(LC3) II/I was unchanged with age, but tended to be lower in iMKO mice than in controls. Markers of liver mitochondrial oxidative capacity and oxidative stress were unchanged with age and iMKO. However, Parkin protein levels in isolated liver mitochondria were 2-fold higher in Aged iMKO mice than in Aged controls. In conclusion, aging had no effect on oxidative capacity and redox stress in the liver. However, aging was associated with increased levels of autophagy and mitophagy markers. Moreover, muscle PGC-1α appears to regulate hepatic mitochondrial translocation of Parkin in aged mice, suggesting that the metabolic capacity of skeletal muscle can modulate mitophagy regulation of the liver during aging.
    Keywords:  Aging; Autophagy; Liver; Metabolism; PGC-1a; Parkin
    DOI:  https://doi.org/10.1016/j.exger.2022.112046
  35. Nat Commun. 2022 Dec 12. 13(1): 7671
    An atlas of late prenatal human neurodevelopment resolved by single-nucleus transcriptomics.
    Susana I Ramos, Zarmeen M Mussa, Elisa N Falk, Balagopal Pai, Bruno Giotti, Kimaada Allette, Peiwen Cai, Fumiko Dekio, Robert Sebra, Kristin G Beaumont, Alexander M Tsankov, Nadejda M Tsankova.
      Late prenatal development of the human neocortex encompasses a critical period of gliogenesis and cortical expansion. However, systematic single-cell analyses to resolve cellular diversity and gliogenic lineages of the third trimester are lacking. Here, we present a comprehensive single-nucleus RNA sequencing atlas of over 200,000 nuclei derived from the proliferative germinal matrix and laminating cortical plate of 15 prenatal, non-pathological postmortem samples from 17 to 41 gestational weeks, and 3 adult controls. This dataset captures prenatal gliogenesis with high temporal resolution and is provided as a resource for further interrogation. Our computational analysis resolves greater complexity of glial progenitors, including transient glial intermediate progenitor cell (gIPC) and nascent astrocyte populations in the third trimester of human gestation. We use lineage trajectory and RNA velocity inference to further characterize specific gIPC subpopulations preceding both oligodendrocyte (gIPC-O) and astrocyte (gIPC-A) lineage differentiation. We infer unique transcriptional drivers and biological pathways associated with each developmental state, validate gIPC-A and gIPC-O presence within the human germinal matrix and cortical plate in situ, and demonstrate gIPC states being recapitulated across adult and pediatric glioblastoma tumors.
    DOI:  https://doi.org/10.1038/s41467-022-34975-2
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