bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024–10–20
fourteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Molecular mechanisms of mitochondrial dynamics.
  2. Clinical and Genetic Spectrum of Patients With Mitochondrial Disease in a Pediatric Egyptian Cohort: Novel Variants and Phenotypic Expansion.
  3. Paroxysmal Non-Kinesigenic Dyskinesias Associated with Biallelic POLG Variants: A Case Report.
  4. Mitophagy as a guardian against cellular aging.
  5. Mitochondrial transplantation: a promising strategy for treating degenerative joint diseases.
  6. Post-transcriptional methylation of mitochondrial-tRNA differentially contributes to mitochondrial pathology.
  7. Enhancing CNS mitophagy: drug development and disease-relevant models.
  8. Cytosolic acetyl-CoA synthesis shields mitochondria from stress in brown adipocytes.
  9. Quantifying constraint in the human mitochondrial genome.
  10. Cell therapy for neurological disorders.
  11. Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.
  12. Mitochondrial DNA copy number and neurocognitive outcomes in children.
  13. Trophoblast-specific overexpression of adiponectin receptor 2 causes fetal growth restriction in pregnant mice.
  14. The Spectrum of clinical manifestations in newborns with the COQ4 mutation: case series and literature review.
  1. Nat Rev Mol Cell Biol. 2024 Oct 17.
    Molecular mechanisms of mitochondrial dynamics.
    Luis-Carlos Tábara, Mayuko Segawa, Julien Prudent.
      Mitochondria not only synthesize energy required for cellular functions but are also involved in numerous cellular pathways including apoptosis, calcium homoeostasis, inflammation and immunity. Mitochondria are dynamic organelles that undergo cycles of fission and fusion, and these transitions between fragmented and hyperfused networks ensure mitochondrial function, enabling adaptations to metabolic changes or cellular stress. Defects in mitochondrial morphology have been associated with numerous diseases, highlighting the importance of elucidating the molecular mechanisms regulating mitochondrial morphology. Here, we discuss recent structural insights into the assembly and mechanism of action of the core mitochondrial dynamics proteins, such as the dynamin-related protein 1 (DRP1) that controls division, and the mitofusins (MFN1 and MFN2) and optic atrophy 1 (OPA1) driving membrane fusion. Furthermore, we provide an updated view of the complex interplay between different proteins, lipids and organelles during the processes of mitochondrial membrane fusion and fission. Overall, we aim to present a valuable framework reflecting current perspectives on how mitochondrial membrane remodelling is regulated.
    DOI:  https://doi.org/10.1038/s41580-024-00785-1
  2. Am J Med Genet A. 2024 Oct 14. e63881
    Clinical and Genetic Spectrum of Patients With Mitochondrial Disease in a Pediatric Egyptian Cohort: Novel Variants and Phenotypic Expansion.
    Hebatallah M Hassaan, Angela Pyle, Nihal Almenabawy, Fiona M Robertson, Nour Elkhateeb, Marian Y Girgis, Iman Gamal El Din Mahmoud, Fawzia Amer, Mona Samaha, Yara Shaheen, Walaa ElNaggar, Doaa Abdoh, Dina Ahmed Mehaney, Iman Ehsan Abdel Meguid, Robert W Taylor, Robert McFarland, Laila Selim.
      Mitochondrial disorders exhibit clinical and genetic diversity. Nearly 400 distinct genes, located in both the mitochondrial and nuclear genomes, harbor pathogenic variants that can produce a broad spectrum of mitochondrial diseases. This work aims to explore the genetic etiology of a cohort of Egyptian pediatric patients who were clinically suspected of having a mitochondrial disorder. A total of 49 patients from 44 unrelated families were studied. Selection criteria included age below 18 years and meeting Morava criteria (a score ≥ 3). The mitochondrial disease criteria (MDC) have been developed to quantify the clinical picture and evaluate the probability of an underlying mitochondrial disorder Exome sequencing, including mitochondrial genome sequencing, was carried out for each participant. Causative variants likely responsible for the phenotypes were identified in 68% of the study population. The mitochondrial subgroup constituted 41% of the studied population with a median age of 4 years. No primary pathogenic variants in mitochondrial DNA were detected. Pathogenic or likely pathogenic variants in eight mitochondrial genes were identified in 78% of the mitochondrial cohort. Additionally, seven novel variants were identified. Nonmitochondrial diagnoses accounted for 27% of the study population. In 32% of cases, disease-causing variants were not identified. The current study underscores the diverse phenotypic and genetic landscape of mitochondrial disorders among Egyptian patients.
    Keywords:  exome sequencing; gene; mitochondrial diseases; variants
    DOI:  https://doi.org/10.1002/ajmg.a.63881
  3. Mov Disord. 2024 Oct 15.
    Paroxysmal Non-Kinesigenic Dyskinesias Associated with Biallelic POLG Variants: A Case Report.
    Barbara Castellotti, Cinzia Gellera, Davide Caputo, Federica Rachele Danti, Giuliana Messina, Marinella Corbetta, Stefania Magri, Franco Taroni, Holger Prokisch, Michael Zech, Giovanna Zorzi.
      
    Keywords:  DNA polymerase gamma (POLG); next generation sequencing (NGS); paroxysmal non‐kinesigenic dystinesias (PNKD)
    DOI:  https://doi.org/10.1002/mds.30029
  4. Autophagy. 2024 Oct 14. 1-3
    Mitophagy as a guardian against cellular aging.
    Tetsushi Kataura, Niall Wilson, Gailing Ma, Viktor I Korolchuk.
      Mitophagy, the selective autophagic clearance of damaged mitochondria, is considered vital for maintaining mitochondrial quality and cellular homeostasis; however, its molecular mechanisms, particularly under basal conditions, and its role in cellular physiology remain poorly characterized. We recently demonstrated that basal mitophagy is a key feature of primary human cells and is downregulated by immortalization, suggesting its dependence on the primary cell state. Mechanistically, we demonstrated that the PINK1-PRKN-SQSTM1 pathway regulates basal mitophagy, with SQSTM1 sensing superoxide-enriched mitochondria through its redox-sensitive cysteine residues, which mediate SQSTM1 oligomerization and mitophagy activation. We developed STOCK1N-57534, a small molecule that targets and promotes this SQSTM1 activation mechanism. Treatment with STOCK1N-57534 reactivates mitophagy downregulated in senescent and naturally aged donor-derived primary cells, improving cellular senescence(-like) phenotypes. Our findings highlight that basal mitophagy is protective against cellular senescence and aging, positioning its pharmacological reactivation as a promising anti-aging strategy.Abbreviation: IR: ionizing radiation; ROS: reactive oxygen species; SARs: selective autophagy receptors.
    Keywords:  Aging; SQSTM1/p62; autophagy; mitochondria; mitophagy; senescence
    DOI:  https://doi.org/10.1080/15548627.2024.2414461
  5. J Transl Med. 2024 Oct 15. 22(1): 941
    Mitochondrial transplantation: a promising strategy for treating degenerative joint diseases.
    Hong Luo, Yue Lai, Weili Tang, Guoyou Wang, Jianlin Shen, Huan Liu.
      The prevalence of age-related degenerative joint diseases, particularly intervertebral disc degeneration and osteoarthritis, is increasing, thereby posing significant challenges for the elderly population. Mitochondrial dysfunction is a critical factor in the etiology and progression of these disorders. Therapeutic interventions that incorporate mitochondrial transplantation exhibit considerable promise by increasing mitochondrial numbers and improving their functionality. Existing evidence suggests that exogenous mitochondrial therapy improves clinical outcomes for patients with degenerative joint diseases. This review elucidates the mitochondrial abnormalities associated with degenerative joint diseases and examines the mechanisms of mitochondrial intercellular transfer and artificial mitochondrial transplantation. Furthermore, therapeutic strategies for mitochondrial transplantation in degenerative joint diseases are synthesized, and the concept of engineered mitochondrial transplantation is proposed.
    Keywords:  Degenerative joint diseases; Engineered mitochondria; Intervertebral disc degeneration; Mitochondrial transplantation; Osteoarthritis
    DOI:  https://doi.org/10.1186/s12967-024-05752-0
  6. Nat Commun. 2024 Oct 18. 15(1): 9008
    Post-transcriptional methylation of mitochondrial-tRNA differentially contributes to mitochondrial pathology.
    Sunita Maharjan, Howard Gamper, Yuka Yamaki, Thomas Christian, Robert Y Henley, Nan-Sheng Li, Takeo Suzuki, Tsutomu Suzuki, Joseph A Piccirilli, Meni Wanunu, Erin Seifert, Douglas C Wallace, Ya-Ming Hou.
      Human mitochondrial tRNAs (mt-tRNAs), critical for mitochondrial biogenesis, are frequently associated with pathogenic mutations. These mt-tRNAs have unusual sequence motifs and require post-transcriptional modifications to stabilize their fragile structures. However, whether a modification that stabilizes a wild-type (WT) mt-tRNA would also stabilize its pathogenic variants is unknown. Here we show that the N1-methylation of guanosine at position 9 (m1G9) of mt-Leu(UAA), while stabilizing the WT tRNA, has a destabilizing effect on variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). This differential effect is further demonstrated, as removal of the m1G9 methylation, while damaging to the WT tRNA, is beneficial to the major pathogenic variant, improving the structure and activity of the variant. These results have therapeutic implications, suggesting that the N1-methylation of mt-tRNAs at position 9 is a determinant of pathogenicity and that controlling the methylation level is an important modulator of mt-tRNA-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-024-53318-x
  7. Trends Pharmacol Sci. 2024 Oct 16. pii: S0165-6147(24)00187-1. [Epub ahead of print]
    Enhancing CNS mitophagy: drug development and disease-relevant models.
    Krishayant S Dhar, Brendan Townsend, Andrew P Montgomery, Jonathan J Danon, Julia K Pagan, Michael Kassiou.
      Mitophagy, the selective degradation of mitochondria, is impaired in many neurodegenerative diseases (NDs), resulting in an accumulation of dysfunctional mitochondria and neuronal damage. Although enhancing mitophagy shows promise as a therapeutic strategy, the clinical significance of mitophagy activators remains uncertain due to limited understanding and poor representation of mitophagy in the central nervous system (CNS). This review explores recent insights into which mitophagy pathways to target and the extent of modulation necessary to be therapeutic towards NDs. We also highlight the complexities of mitophagy in the CNS, highlighting the need for disease-relevant models. Last, we outline crucial aspects of in vitro models to consider during drug discovery, aiming to bridge the gap between preclinical research and clinical applications in treating NDs through mitophagy modulation.
    Keywords:  central nervous system; clinical relevance; disease models; drug development; mitochondrial dysfunction; mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.tips.2024.09.002
  8. Nat Metab. 2024 Oct 15.
    Cytosolic acetyl-CoA synthesis shields mitochondria from stress in brown adipocytes.
      
    DOI:  https://doi.org/10.1038/s42255-024-01152-2
  9. Nature. 2024 Oct 16.
    Quantifying constraint in the human mitochondrial genome.
    Nicole J Lake, Kaiyue Ma, Wei Liu, Stephanie L Battle, Kristen M Laricchia, Grace Tiao, Daniela Puiu, Kenneth K Ng, Justin Cohen, Alison G Compton, Shannon Cowie, John Christodoulou, David R Thorburn, Hongyu Zhao, Dan E Arking, Shamil R Sunyaev, Monkol Lek.
      Mitochondrial DNA (mtDNA) has an important yet often overlooked role in health and disease. Constraint models quantify the removal of deleterious variation from the population by selection and represent powerful tools for identifying genetic variation that underlies human phenotypes1-4. However, nuclear constraint models are not applicable to mtDNA, owing to its distinct features. Here we describe the development of a mitochondrial genome constraint model and its application to the Genome Aggregation Database (gnomAD), a large-scale population dataset that reports mtDNA variation across 56,434 human participants5. Specifically, we analyse constraint by comparing the observed variation in gnomAD to that expected under neutrality, which was calculated using a mtDNA mutational model and observed maximum heteroplasmy-level data. Our results highlight strong depletion of expected variation, which suggests that many deleterious mtDNA variants remain undetected. To aid their discovery, we compute constraint metrics for every mitochondrial protein, tRNA and rRNA gene, which revealed a range of intolerance to variation. We further characterize the most constrained regions within genes through regional constraint and identify the most constrained sites within the entire mitochondrial genome through local constraint, which showed enrichment of pathogenic variation. Constraint also clustered in three-dimensional structures, which provided insight into functionally important domains and their disease relevance. Notably, we identify constraint at often overlooked sites, including in rRNA and noncoding regions. Last, we demonstrate that these metrics can improve the discovery of deleterious variation that underlies rare and common phenotypes.
    DOI:  https://doi.org/10.1038/s41586-024-08048-x
  10. Nat Med. 2024 Oct;30(10): 2756-2770
    Cell therapy for neurological disorders.
    Soshana P Svendsen, Clive N Svendsen.
      Cell therapies for neurological disorders are entering the clinic and present unique challenges and opportunities compared with conventional medicines. They have the potential to replace damaged nervous tissue and integrate into the brain or spinal cord to produce functional effects for the lifetime of the patient, which could revolutionize the way clinicians treat debilitating neurological disorders. The major challenge has been cell sourcing, which historically relied mainly on fetal brain tissue. This has largely been overcome with the advent of pluripotent stem cell technology and the ability to make almost any cell of the nervous system at scale. Furthermore, advances in gene editing now allow the generation of genetically modified cells that could perform better and evade the immune system. With all the remarkable new approaches to treat neurological disorders, we take a critical look at the state of current clinical trials and how challenges may be overcome with the evolving technology and innovation occurring in the stem cell field.
    DOI:  https://doi.org/10.1038/s41591-024-03281-3
  11. Nat Metab. 2024 Oct 15.
    Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.
    Shane M O'Carroll, Christian G Peace, Juliana E Toller-Kawahisa, Yukun Min, Alexander Hooftman, Sara Charki, Louise Kehoe, Maureen J O'Sullivan, Aline Zoller, Anne F Mcgettrick, Emily A Day, Maria Simarro, Neali Armstrong, Justin P Annes, Luke A J O'Neill.
      Itaconate is one of the most highly upregulated metabolites in inflammatory macrophages and has been shown to have immunomodulatory properties. Here, we show that itaconate promotes type I interferon production through inhibition of succinate dehydrogenase (SDH). Using pharmacological and genetic approaches, we show that SDH inhibition by endogenous or exogenous itaconate leads to double-stranded mitochondrial RNA (mtRNA) release, which is dependent on the mitochondrial pore formed by VDAC1. In addition, the double-stranded RNA sensors MDA5 and RIG-I are required for IFNβ production in response to SDH inhibition by itaconate. Collectively, our data indicate that inhibition of SDH by itaconate links TCA cycle modulation to type I interferon production through mtRNA release.
    DOI:  https://doi.org/10.1038/s42255-024-01145-1
  12. Pediatr Res. 2024 Oct 16.
    Mitochondrial DNA copy number and neurocognitive outcomes in children.
    Pei Wen Tung, Tessa R Bloomquist, Andrea A Baccarelli, Julie B Herbstman, Virginia Rauh, Frederica Perera, Jeff Goldsmith, Amy Margolis, Allison Kupsco.
       BACKGROUND: Low mitochondria DNA copy number (mtDNAcn) has been linked to cognitive decline. However, the role of mtDNAcn in healthy cognitive development is unclear. We hypothesized early-life mtDNAcn would be associated with children's learning and memory.
    METHODS: We quantified mtDNAcn in umbilical cord blood and child blood at ages 5-7 from participants in a prospective birth cohort. We administered the Children's Memory Scale (CMS) at ages 9-14 (N = 342) and the Wechsler Intelligence Scale for Children (WISC-IV) at ages 7 and 9 (N = 457). Associations between mtDNAcn tertiles and CMS and WISC were evaluated with linear regression and linear mixed-effects models, respectively. We examined non-linear associations using generalized additive mixed models.
    RESULTS: Relative to the middle tertile of mtDNAcn, lower childhood mtDNAcn was associated with lower WISC Working Memory (β = -2.65, 95% CI [-5.24, -0.06]) and Full-Scale IQ (β = -3.71 [-6.42, -1.00]), and higher CMS Visual Memory (β = 4.70 [0.47, 8.93]). Higher childhood mtDNAcn was linked to higher CMS Verbal Memory (β = 7.75 [2.50, 13.01]). In non-linear models, higher childhood mtDNAcn was associated with lower WISC Verbal Comprehension.
    CONCLUSIONS: Our study provides novel evidence that mtDNAcn measured in childhood is associated with children's neurocognitive performance. mtDNAcn may be a marker of healthy child development.
    IMPACT: Mitochondrial DNA copy number (mtDNAcn) may serve as a biomarker for early-life neurocognitive performances in the children's population. Both low and high mtDNAcn may contribute to poorer neurocognition, reflected through learning and memory abilities. This research elucidated the importance of investigating mitochondrial biomarkers in healthy populations and facilitated advancements of future studies to better understand the associations between mitochondrial markers and adverse children's health outcomes.
    DOI:  https://doi.org/10.1038/s41390-024-03653-y
  13. FASEB J. 2024 Oct 15. 38(19): e70100
    Trophoblast-specific overexpression of adiponectin receptor 2 causes fetal growth restriction in pregnant mice.
    Jerad H Dumolt, Fredrick J Rosario, Kenneth Barentsen, Johann Urschitz, Theresa L Powell, Thomas Jansson.
      Maternal obesity in pregnancy is strongly associated with complications such as fetal overgrowth and infants of obese mothers have an increased risk to develop obesity, diabetes, and cardiovascular disease later in life. However, the underlying mechanisms are not well established. Circulating levels of adiponectin are low in obese pregnant women and maternal circulating adiponectin is negatively associated with birth weight. We have reported that normalizing maternal adiponectin in obese pregnant mice prevents placental dysfunction, fetal overgrowth, and programming of offspring cardio-metabolic disease. However, the mechanistic link between maternal adiponectin, placental function, and fetal growth remains to be established. We hypothesized that trophoblast-specific overexpression of the adiponectin receptor 2 (Adipor2) in healthy pregnant mice inhibits placental mTORC1 signaling and nutrient transport, resulting in fetal growth restriction. Using lentiviral transduction of blastocysts with a mammalian gene expression lentiviral vector for up-regulation of Adipor2 (Adipor2-OX), we achieved a ~ 3-fold increase in placenta Adipor2 mRNA levels and a 2-fold increase of the ADIPOR2 protein in the trophoblast plasma membrane. Placenta-specific Adipor2-OX increased placental peroxisome proliferator-activated receptor-α phosphorylation, ceramide synthase expression and ceramide concentrations. Furthermore, Adipor2-OX inhibited placental mTORC1 signaling and reduced in vivo placental transport of glucose and amino acids. Lastly, Adipor2-OX reduced fetal weight by 11%. These data provide mechanistic evidence that placental Adipor2 signaling directly affects fetal growth. We propose that low circulating adiponectin in maternal obesity causes fetal overgrowth and programs the offspring for cardio-metabolic disease mediated by a direct effect on placental function.
    Keywords:  PPARα; insulin signaling; mTOR; maternal–fetal exchange; placenta
    DOI:  https://doi.org/10.1096/fj.202302143R
  14. Front Pediatr. 2024 ;12 1410133
    The Spectrum of clinical manifestations in newborns with the COQ4 mutation: case series and literature review.
    Pianpian Pan, Na Zhou, Yi Sun, Zhengrong Chen, Jin Han, Wei Zhou.
       Background: Coenzyme Q10 (CoQ10) plays an important role in the electron transport chain within the human mitochondrial respiratory chain. The manifestations of this deficiency exhibit a diverse range. This study investigates the clinical manifestations of primary coenzyme Q10 deficiency in neonates with the COQ4 mutation to improve the diagnosis of the disease and the prognosis through targeted treatment.
    Methods: We report 4 patients with primary coenzyme Q10 deficiency by COQ4 variants in neonates. A comprehensive literature search and review for original articles and case reports with COQ4 mutation published from January 1989 to November 2023 was performed through Pubmed. We review clinical manifestations, diagnostic approaches, and treatment monitoring in these and 20 previously reported patients.
    Results: Within the cohort of four cases examined, three females and one male were identified from two distinct families. Specifically, case 1 and 2 consisted of monoamniotic twins. Cases 3 and 4 were siblings. A comprehensive review of 20 cases involving neonatal-onset COQ4 mutation was conducted. Half of the cases are Chinese. There was no statistically significant difference in the mortality between Chinese (9/12, 75%) and other regions (11/12, 91.7%) (P = 0.27). The survival time for the 24 cases was 60.0 ± 98.0 days (95% confidence interval CI: 0-252.0 days). The incidence of prenatal abnormalities in preterm infants was significantly higher than that in full-term infants (66.7% vs. 16.7%, P = 0.02). Hyperlactatemia was one of the most common manifestations, accounting for 75% of cases (18/24). Twenty of the 24 cases were diagnosed by whole exome sequencing. Only 9 patients received exogenous coenzyme Q10 treatment, and all the 4 surviving patients received coenzyme Q10 supplementation.
    Conclusion: The prognosis of COQ4 mutation in the neonatal period indicates a low survival rate and an poor prognosis. This may be due to the incomplete understanding of the mechanism of how COQ4 gene defects lead to coenzyme Q10 deficiency and why CoQ10 supplementation does not respond well to treatment. To improve the diagnostic rate, in addition to genetic testing, mitochondrial functional verification should be prioritized in southern China, where the incidence is relatively high. It will facilitate more in-depth mechanistic studies.
    Keywords:  COQ4; CoQ10; mitochondrial disorder; newborn; primary coenzyme Q10 deficiency
    DOI:  https://doi.org/10.3389/fped.2024.1410133
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:23.