bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024–11–24
twenty-one papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease.
  2. WDR45-related encephalopathy mimicking Leigh syndrome associated with complex I deficiency: a case report.
  3. AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.
  4. Respiratory Chain Complex I Deficiency in Leber Hereditary Optic Neuropathy: Insights from Ophthalmologic and Molecular Investigations in Tunisia.
  5. PDE12 mediated pruning of the poly-A tail of mitochondrial DNA-encoded tRNAs is essential for survival.
  6. Mitochondrial plasticity: An emergent concept in neuronal plasticity and memory.
  7. Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome.
  8. De novo missense variants in the PP2A regulatory subunit PPP2R2B in a neurodevelopmental syndrome: potential links to mitochondrial dynamics and spinocerebellar ataxias.
  9. AMPK regulates the maintenance and remodelling of the neuromuscular junction.
  10. TET3 regulates terminal cell differentiation at the metabolic level.
  11. Defective Neurogenesis in Lowe Syndrome is Caused by Mitochondria Loss and Cilia-related Sonic Hedgehog Defects.
  12. The Role of Cardiolipin in Brain Bioenergetics, Neuroinflammation, and Neurodegeneration.
  13. Starvation-induced metabolic rewiring affects mTORC1 composition in vivo.
  14. Textbook oxidative phosphorylation needs to be rewritten.
  15. Hypothyroidism modulates mitochondrial dynamics and mitophagy in the heart of rats under fed and fasting conditions.
  16. Overview of reproductive and pregnancy health principles and practice used by maternal-fetal medicine specialists for fetal-neonatal neurology consultants.
  17. Advances in AAV-mediated gene replacement therapy for pediatric monogenic neurological disorders.
  18. Disordered electron transfer: New forms of defective steroidogenesis and mitochondriopathy.
  19. Switching of RNA splicing regulators in immature neuroblasts during adult neurogenesis.
  20. Mitochondrial DAMPs: Key mediators in neuroinflammation and neurodegenerative disease pathogenesis.
  21. NOTCH1 mitochondria localization during heart development promotes mitochondrial metabolism and the endothelial-to-mesenchymal transition in mice.
  1. EMBO Mol Med. 2024 Nov 20.
    Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease.
    Lindsey Van Haute, Petra Páleníková, Jia Xin Tang, Pavel A Nash, Mariella T Simon, Angela Pyle, Monika Oláhová, Christopher A Powell, Pedro Rebelo-Guiomar, Alexander Stover, Michael Champion, Charulata Deshpande, Emma L Baple, Karen L Stals, Sian Ellard, Olivia Anselem, Clémence Molac, Giulia Petrilli, Laurence Loeuillet, Sarah Grotto, Tania Attie-Bitach, Jose E Abdenur, Robert W Taylor, Michal Minczuk.
      Pathogenic variants in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial function. Within this group, an increasing number of families have been identified, where Mendelian genetic disorders implicate defective mitochondrial RNA biology. The PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs. Here, we report that disease-causing PDE12 variants in three unrelated families are associated with mitochondrial respiratory chain deficiencies and wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. Whole exome sequencing of affected probands revealed novel, segregating bi-allelic missense PDE12 variants affecting conserved residues. Patient-derived primary fibroblasts demonstrate diminished steady-state levels of PDE12 protein, whilst mitochondrial poly(A)-tail RNA sequencing (MPAT-Seq) revealed an accumulation of spuriously polyadenylated mitochondrial RNA, consistent with perturbed function of PDE12 protein. Our data suggest that PDE12 regulates mitochondrial RNA processing and its loss results in neurological and muscular phenotypes.
    Keywords:  Exome Sequencing; Lactic Acidosis; Mitochondrial Disease; RNA Processing; tRNA
    DOI:  https://doi.org/10.1038/s44321-024-00172-5
  2. Eur J Hum Genet. 2024 Nov 22.
    WDR45-related encephalopathy mimicking Leigh syndrome associated with complex I deficiency: a case report.
    Giulia Ferrera, Kevork Derderian, Rossella Izzo, Barbara Gnutti, Andrea Legati, Giovanna Zorzi, Eleonora Lamantea, Arcangela Iuso, Anna Ardissone.
      Pathogenic WDR45 variants cause neurodevelopmental disorders (NDDs) including β-propeller protein-associated neurodegeneration (BPAN), characterized by developmental delay (DD), ataxia and extrapyramidal signs. Our patient, initially presenting at 22 months with DD, now, aged 7, shows intellectual disability, ataxia and rigidity. MRI findings were suggestive of Leigh syndrome, a mitochondrial disorder (MD) phenotype, with no brain iron accumulation. Reduced activity of respiratory chain complex I (cI) and complex II (cII) was identified in muscle and fibroblasts, and a cII reduction in muscle only; however, a primary MD was excluded. Exome sequencing revealed a de novo pathogenic WDR45 variant. Autophagic flux analysis showed a mildly reduced p62 response, with normal autophagy progression. This is the first report linking WDR45 to cI assembly and activity, indicating mitochondrial dysfunction as a potential pathophysiological BPAN mechanism. We recommend considering WDR45-related NDDs when diagnosing early-onset NDDs, particularly Leigh-like encephalopathies with cI deficiency, even without brain iron accumulation.
    DOI:  https://doi.org/10.1038/s41431-024-01745-1
  3. Mol Cell. 2024 Nov 21. pii: S1097-2765(24)00880-3. [Epub ahead of print]84(22): 4261-4263
    AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.
    Hui Jiang.
      In this issue of Molecular Cell, Longo et al.1 reveal that AMPK, a regulatory kinase activated by metabolic stress, inhibits NIX/BNIP3-dependent mitophagy to preserve mitochondrial quantity and activates PINK1/Parkin-dependent mitophagy to ensure mitochondrial quality.
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.040
  4. BMC Genomics. 2024 Nov 22. 25(1): 1133
    Respiratory Chain Complex I Deficiency in Leber Hereditary Optic Neuropathy: Insights from Ophthalmologic and Molecular Investigations in Tunisia.
    Latifa Chkioua, Yessine Amri, Chayma Sahli, Tawfik Nasri, Mohamed Omar Miladi, Taieb Massoud, Sandrine Laradi, Mohamed Ghorbel, Hassen Ben Abdennebi.
       BACKGROUND: Leber hereditary optic neuropathy (LHON) is a mitochondrial DNA (mtDNA) rare disease due to the pathogenic variant of the NADH dehydrogenase enzyme. LHON is characterized by a sudden central vision loss due to focal degeneration of the retinal ganglion cell layer and optic nerve. Symptoms usually appear between the age of 18 and 35 years. Some individuals present the mtDNA mutations but not presented the LHON clinical features. The heteroplasmic or homoplasmic character of the mutations among patients explains why they develop the disease or not even though they carry the pathogenic variant.
    METHODS: This study was performed in collaboration with the department of ophthalmology of Farhat Hached Hospital, Sousse, Tunisia. Screening for the common mutations in Mt-ND1 gene (m.3460G > A), Mt-ND4 gene (m.11778G > A) and Mt-ND6 gene (m.14484T > C) was performed in five Tunisian families by standard RFLP PCR, followed by direct sequencing of the entire of these genes. Indeed, bioinformatics tools were used to predict the potential functional impact of the identified mutations on the Human mitochondrial respiratory complex I protein.
    RESULTS: one novel p.L601M (m.1413 C > A) and four previously reported mutations were identified in this study including: rs199476112G > A (m.11778G > A); rs202227543G > A (m.14258G > A); rs1603224763 (m.14510 dup) and NC_012920.1: m.3244G > C. In this present report, only one patient was found carrying the primary point mutation (m. 11778G > A). The ophthalmologic findings showing major fundus changes included hyperemic optic discs; disc pseudo-oedema and microangiopathy leading to optic disc atrophy. The analyses of the stability of protein upon identified mutations using DynaMut tool server demonstrated that these variations induce a rigidification in the region where they are located.
    CONCLUSION: This is the first Tunisian report of mtDNA mutations identified in Tunisia causing the LHON. The main factors involved in the pathophysiological mechanisms of this disease are genetic, epigenetic, hormonal and environmental influences.
    Keywords:  Leber hereditary optic neuropathy; Mitochondrial DNA; Mutations; Pathophysiological mechanisms
    DOI:  https://doi.org/10.1186/s12864-024-11060-0
  5. EMBO Mol Med. 2024 Nov 20.
    PDE12 mediated pruning of the poly-A tail of mitochondrial DNA-encoded tRNAs is essential for survival.
    Chenxiao Yu, Marco Tigano, Erin L Seifert.
      
    DOI:  https://doi.org/10.1038/s44321-024-00171-6
  6. Neurobiol Dis. 2024 Nov 16. pii: S0969-9961(24)00342-5. [Epub ahead of print] 106740
    Mitochondrial plasticity: An emergent concept in neuronal plasticity and memory.
    Typhaine Comyn, Thomas Preat, Alice Pavlowsky, Pierre-Yves Plaçais.
      Mitochondria are classically viewed as 'on demand' energy suppliers to neurons in support of their activity. In order to adapt to a wide range of demands, mitochondria need to be highly dynamic and capable of adjusting their metabolic activity, shape, and localization. Although these plastic properties give them a central support role in basal neuronal physiology, recent lines of evidence point toward a role for mitochondria in the regulation of high-order cognitive functions such as memory formation. In this review, we discuss the interplay between mitochondrial function and neural plasticity in sustaining memory formation at the molecular and cellular levels. First, we explore the global significance of mitochondria in memory formation. Then, we will detail the memory-relevant cellular and molecular mechanisms of mitochondrial plasticity. Finally, we focus on those mitochondrial functions, including but not limited to ATP production, that give mitochondria their pivotal role in memory formation. Altogether, this review highlights the central role of mitochondrial structural and functional plasticity in supporting and regulating neuronal plasticity and memory.
    Keywords:  Energy; Glia; Memory; Mitochondria dynamics; TCA cycle
    DOI:  https://doi.org/10.1016/j.nbd.2024.106740
  7. Cell Metab. 2024 Nov 14. pii: S1550-4131(24)00403-0. [Epub ahead of print]
    Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome.
    Shen Li, Hongbo Liu, Hailong Hu, Eunji Ha, Praveena Prasad, Brenita C Jenkins, Ujjalkumar Subhash Das, Sarmistha Mukherjee, Kyosuke Shishikura, Renming Hu, Daniel J Rader, Liming Pei, Joseph A Baur, Megan L Matthews, Garret A FitzGerald, Melanie R McReynolds, Katalin Susztak.
      The understanding of cardiovascular-kidney-metabolic syndrome remains difficult despite recently performed large scale genome-wide association studies. Here, we identified beta-lactamase (LACTB), a novel gene whose expression is targeted by genetic variations causing kidney dysfunction and hyperlipidemia. Mice with LACTB deletion developed impaired glucose tolerance, elevated lipid levels, and increased sensitivity to kidney disease, while mice with tubule-specific overexpression of LACTB were protected from kidney injury. We show that LACTB is a novel mitochondrial protease cleaving and activating phospholipase A2 group VI (PLA2G6), a kidney-metabolic risk gene itself. Genetic deletion of PLA2G6 in tubule-specific LACTB-overexpressing mice abolished the protective function of LACTB. Via mouse and human lipidomic studies, we show that LACTB and downstream PLA2G6 convert oxidized phosphatidylethanolamine to lyso-phosphatidylethanolamine and thereby regulate mitochondrial function and ferroptosis. In summary, we identify a novel gene and a core targetable pathway for kidney-metabolic disorders.
    Keywords:  GWAS; cardiovascular-kidney-metabolic syndrome; ferroptosis; genetics; kidney disease; mitochondria; phospholipase; phospholipid; serine protease
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.007
  8. Hum Mol Genet. 2024 Nov 20. pii: ddae166. [Epub ahead of print]
    De novo missense variants in the PP2A regulatory subunit PPP2R2B in a neurodevelopmental syndrome: potential links to mitochondrial dynamics and spinocerebellar ataxias.
    Priyanka Sandal, Chian Ju Jong, Ronald A Merrill, Grace J Kollman, Austin H Paden, Eric G Bend, Jennifer Sullivan, Rebecca C Spillmann, Vandana Shashi, Anneke T Vulto-van Silfhout, Rolph Pfundt, Bert B A de Vries, Pan P Li, Louise S Bicknell, Stefan Strack.
      The heterotrimeric protein phosphatase 2A (PP2A) complex catalyzes about half of Ser/Thr dephosphorylations in eukaryotic cells. A CAG repeat expansion in the neuron-specific protein PP2A regulatory subunit PPP2R2B gene causes spinocerebellar ataxia type 12 (SCA12). We established five monoallelic missense variants in PPP2R2B (four confirmed as de novo) as a cause of intellectual disability with developmental delay (R149P, T246K, N310K, E37K, I427T). In addition to moderate to severe intellectual disability and developmental delay, affected individuals presented with seizures, microcephaly, aggression, hypotonia, as well as broad-based or stiff gait. We used biochemical and cellular assays, including a novel luciferase complementation assay to interrogate PP2A holoenzyme assembly and activity, as well as deregulated mitochondrial dynamics as possible pathogenic mechanisms. Cell-based assays documented impaired ability of PPP2R2B missense variants to incorporate into the PP2A holoenzyme, localize to mitochondria, induce fission of neuronal mitochondria, and dephosphorylate the mitochondrial fission enzyme dynamin-related protein 1. AlphaMissense-based pathogenicity prediction suggested that an additional seven unreported missense variants may be pathogenic. In conclusion, our studies identify loss-of-function at the PPP2R2B locus as the basis for syndromic intellectual disability with developmental delay. They also extend PPP2R2B-related pathologies from neurodegenerative (SCA12) to neurodevelopmental disorders and suggests that altered mitochondrial dynamics may contribute to mechanisms.
    Keywords:  cerebellar ataxias; dynamin-related protein 1; mitochondrial dynamics; neurodevelopmental disorders; protein phosphatase 2A
    DOI:  https://doi.org/10.1093/hmg/ddae166
  9. Mol Metab. 2024 Nov 19. pii: S2212-8778(24)00197-2. [Epub ahead of print] 102066
    AMPK regulates the maintenance and remodelling of the neuromuscular junction.
    Sean Y Ng, Andrew I Mikhail, Stephanie R Mattina, Salah A Mohammed, Shahzeb K Khan, Eric M Desjardins, Changhyun Lim, Stuart M Phillips, Gregory R Steinberg, Vladimir Ljubicic.
      The neuromuscular junction (NMJ) is an electrochemical signaling apparatus essential for facilitating muscle contraction and counteracting neurodegenerative processes associated with aging and neuromuscular disorders. Although our understanding of the molecular mechanisms that govern the maintenance and plasticity of the NMJ is limited, recent evidence suggests that AMP-activated protein kinase (AMPK) is an emerging, influential player. Our findings reveal an increased abundance of AMPK transcripts within the NMJ and an age-associated decline in AMPK activity and synapse-specific mitochondrial gene expression. Young mice null for skeletal muscle AMPK displayed a neuromuscular phenotype akin to aged animals. Pharmacological AMPK stimulation facilitated its localization in subsynaptic myonuclei, preceded the induction of several NMJ-related transcripts, and enhanced myotube acetylcholine receptor clustering. Exercise-induced AMPK activation in mouse muscle elicited a broad NMJ-related gene response, consistent with human exercise data. Together, these findings highlight a role for AMPK in the maintenance and remodeling of the NMJ.
    Keywords:  Mitochondria; PGC-1α; acetylcholine receptors; aging; exercise
    DOI:  https://doi.org/10.1016/j.molmet.2024.102066
  10. Nat Commun. 2024 Nov 18. 15(1): 9749
    TET3 regulates terminal cell differentiation at the metabolic level.
    Isabel Mulet, Carmen Grueso-Cortina, Mireia Cortés-Cano, Daniela Gerovska, Guangming Wu, Stefania Alexandra Iakab, Daniel Jimenez-Blasco, Andrea Curtabbi, Pablo Hernansanz-Agustín, Harmony Ketchum, Israel Manjarrés-Raza, F Thomas Wunderlich, Juan Pedro Bolaños, Meelad M Dawlaty, Carsten Hopf, José Antonio Enríquez, Marcos J Araúzo-Bravo, Natalia Tapia.
      TET-family members play a critical role in cell fate commitment. Indeed, TET3 is essential to postnatal development due to yet unknown reasons. To define TET3 function in cell differentiation, we have profiled the intestinal epithelium at single-cell level from wild-type and Tet3 knockout mice. We have found that Tet3 is mostly expressed in differentiated enterocytes. In the absence of TET3, enterocytes exhibit an aberrant differentiation trajectory and do not acquire a physiological cell identity due to an impairment in oxidative phosphorylation, specifically due to an ATP synthase assembly deficiency. Moreover, spatial metabolomics analysis has revealed that Tet3 knockout enterocytes exhibit an unphysiological metabolic profile when compared with their wild-type counterparts. In contrast, no metabolic differences have been observed between both genotypes in the stem cell compartment where Tet3 is mainly not expressed. Collectively, our findings suggest a mechanism by which TET3 regulates mitochondrial function and, thus, terminal cell differentiation at the metabolic level.
    DOI:  https://doi.org/10.1038/s41467-024-54044-0
  11. bioRxiv. 2024 Nov 01. pii: 2024.11.01.621496. [Epub ahead of print]
    Defective Neurogenesis in Lowe Syndrome is Caused by Mitochondria Loss and Cilia-related Sonic Hedgehog Defects.
    Chien-Hui Lo, Siyu Chen, Jingyu Zhao, Zhiquan Liu, Biao Wang, Qing Wang, Tia J Kowal, Yang Sun.
      Human brain development is a complex process that requires intricate coordination of multiple cellular and developmental events. Dysfunction of lipid metabolism can lead to neurodevelopmental disorders. Lowe syndrome (LS) is a recessive X-linked disorder associated with proximal tubular renal disease, congenital cataracts and glaucoma, and central nervous system developmental delays. Mutations in OCRL, which encodes an inositol polyphosphate 5-phosphatase, lead to the development of LS. The cellular mechanism responsible for neuronal dysfunction in LS is unknown. Here we show depletion of mitochondrial DNA and decrease in mitochondrial activities result in neuronal differentiation defects. Increased astrocytes, which are secondary responders to neurodegeneration, are observed in neuronal (iN) cells differentiated from Lowe patient-derived iPSCs and an LS mouse model. Inactivation of cilia-related sonic hedgehog signaling, which organizes the pattern of cellular neuronal differentiation, is observed in an OCRL knockout, iN cells differentiated from Lowe patient-derived iPSCs, and an LS mouse model. Taken together, our findings indicate that mitochondrial dysfunction and impairment of the ciliary sonic hedgehog signaling pathway represent a novel pathogenic mechanism underlying the disrupted neuronal differentiation observed in LS.
    DOI:  https://doi.org/10.1101/2024.11.01.621496
  12. Mol Neurobiol. 2024 Nov 19.
    The Role of Cardiolipin in Brain Bioenergetics, Neuroinflammation, and Neurodegeneration.
    Patrick C Bradshaw, Jessa L Aldridge, Leah E Jamerson, Canah McNeal, A Catherine Pearson, Chad R Frasier.
      Cardiolipin (CL) is an essential phospholipid that supports the functions of mitochondrial membrane transporters and oxidative phosphorylation complexes. Due to the high level of fatty acyl chain unsaturation, CL is prone to peroxidation during aging, neurodegenerative disease, stroke, and traumatic brain or spinal cord injury. Therefore, effective therapies that stabilize and preserve CL levels or enhance healthy CL fatty acyl chain remodeling are needed. In the last few years, great strides have been made in determining the mechanisms through which precursors for CL biosynthesis, such as phosphatidic acid (PA), are transferred from the ER to the outer mitochondrial membrane (OMM) and then to the inner mitochondrial membrane (IMM) where CL biosynthesis takes place. Many neurodegenerative disorders show dysfunctional mitochondrial ER contact sites that may perturb PA transport and CL biosynthesis. However, little is currently known on how neuronal mitochondria regulate the synthesis, remodeling, and degradation of CL. This review will focus on recent developments on the role of CL in neurological disorders. Importantly, due to CL species in the brain being more unsaturated and diverse than in other tissues, this review will also identify areas where more research is needed to determine a complete picture of brain and spinal cord CL function so that effective therapeutics can be developed to restore the rates of CL synthesis and remodeling in neurological disorders.
    Keywords:  Alzheimer’s; Cardiolipin; Cell death; Inflammation; Mitochondria; Parkinson’s
    DOI:  https://doi.org/10.1007/s12035-024-04630-6
  13. Sci Rep. 2024 11 16. 14(1): 28296
    Starvation-induced metabolic rewiring affects mTORC1 composition in vivo.
    Kaade Edgar, Mausbach Simone, Erps Nina, Sylvester Marc, Shakeri Farhad, Ron D Jachimowicz, Gieselmann Volkmar, Thelen Melanie.
      Lysosomes play a crucial role in metabolic adaptation to starvation, but detailed in vivo studies are scarce. Therefore, we investigated the changes of the proteome of liver lysosomes in mice starved short-term for 6h or long-term for 24h. We verified starvation-induced catabolism by weight loss, ketone body production, drop in blood glucose and an increase of 3-methylhistidine. Deactivation of mTORC1 in vivo after short-term starvation causes a depletion of mTORC1 and the associated Ragulator complex in hepatic lysosomes, resulting in diminished phosphorylation of mTORC1 target proteins. While mTORC1 lysosomal protein levels and activity in liver were restored after long-term starvation, the lysosomal levels of Ragulator remained constantly reduced. To determine whether this mTORC1 activity pattern may be organ-specific, we further investigated the key metabolic organs muscle and brain. mTORC1 inactivation, but not re-activation, occurred in muscle after a starvation of 12 h or longer. In brain, mTORC1 activity remained unchanged during starvation. As mTORC1 deactivation is known to induce autophagy, we further investigated the more than 150 non-lysosomal proteins enriched in the lysosomal fraction upon starvation. Proteasomal, cytosolic and peroxisomal proteins dominated after short-term starvation, while after long-term starvation, mainly proteasomal and mitochondrial proteins accumulated, indicating ordered autophagic protein degradation.
    DOI:  https://doi.org/10.1038/s41598-024-78873-7
  14. Trends Biochem Sci. 2024 Nov 21. pii: S0968-0004(24)00254-8. [Epub ahead of print]
    Textbook oxidative phosphorylation needs to be rewritten.
    Alicia J Kowaltowski, Fernando Abdulkader.
      Oxidative phosphorylation (OxPhos) is the energy-transfer process that generates most of our ATP, fueled by proton and electrical gradients across the inner mitochondrial membrane. A new surprising finding by Hernansanz-Agustín et al. demonstrates that between one-third and half of this gradient is attributable to Na+, transported in exchange for protons within complex I.
    Keywords:  complex I; ion transport; mitochondria; oxidative phosphorylation; sodium–proton exchange
    DOI:  https://doi.org/10.1016/j.tibs.2024.11.002
  15. Life Sci. 2024 Nov 15. pii: S0024-3205(24)00844-0. [Epub ahead of print]359 123254
    Hypothyroidism modulates mitochondrial dynamics and mitophagy in the heart of rats under fed and fasting conditions.
    Juliana Santos Romão, Jessika Geisebel Oliveira Neto, Cherley Borba Vieira Andrade, Jorge José Carvalho, Carmen Cabanelas Pazos-Moura, Karen Jesus Oliveira.
       AIMS: Investigate the impact of hypothyroidism on mitochondrial dynamics and mitophagy in the heart under fed and fasting conditions.
    METHODS: Hypothyroidism was induced in male Wistar rats with methimazole (0.03 %) for 21 days. Half of the euthyroid and hypothyroid groups underwent a 48-h fasting. Mitochondrial number and ultrastructure were evaluated by transmission electron microscopy. Fusion, fission, mitophagy, oxidative stress, and mitochondrial oxidative phosphorylation system (OXPHOS) components were analyzed by Western Blot and qPCR.
    RESULTS: Hypothyroidism increased DRP1 activation and the p-DRP1/OPA1 ratio, indicating a shift toward mitochondrial fission over fusion. Under fasting, hypothyroidism prevented the increases in mitochondrial size, elongation, OPA1, and OXPHOS seen in euthyroid fasted rats. Hypothyroidism also raised 4-HNE content, an oxidative stress product, increased mitochondrial injury, and exacerbated fasting-related mitochondrial damage. This was accompanied by elevated Parkin levels in both fed and fasted hypothyroid groups, but without changes in PINK1 levels or Parkin activation. While fasting upregulated Bnip3l and Map1lc3b expression in euthyroid rats, hypothyroidism suppressed this response, though it did not prevent fasting-induced Bnip3 increases.
    CONCLUSIONS: Hypothyroidism increases the activation of mitochondrial fission machinery and oxidative stress, and induces mitochondrial damage without activation of mitophagy proteins, suggesting disrupted mitophagy signaling. It also interferes with fasting-induced mitochondrial dynamics adaptations, highlighting the essential role of thyroid hormones in metabolic adaptation to fasting.
    Keywords:  Autophagy; Fission; Fusion; Mitochondria; Thyroid hormone
    DOI:  https://doi.org/10.1016/j.lfs.2024.123254
  16. Semin Fetal Neonatal Med. 2024 Nov 12. pii: S1744-165X(24)00037-4. [Epub ahead of print] 101555
    Overview of reproductive and pregnancy health principles and practice used by maternal-fetal medicine specialists for fetal-neonatal neurology consultants.
    Nancy Soliman, Verena Kuret, Elaine Chan, Christopher Smith, Mary-Anne Thomas, Houman Mahallati, Heidi Grosjean, Erika Friebe, Leah Rusnell.
      Unique from other fetal anatomical systems, the central nervous system (CNS) starts development early in the embryonic period shortly after fertilization before most patients are even aware they are pregnant. Maturation throughout pregnancy involve complicated structural and functional changes, most likely below the resolution of testing to detect. During this time, the fetal CNS is susceptible to lesions that reflect trimester-specific adverse events. Neonatal neurological status with childhood sequelae can result from combinations of antenatal, peripartum and neonatal adverse events. Person-specific clinical management choices must consider the timing of multiple mechanisms that can alter neurodevelopment including genetic causes, aetiologies after conception as well as communicable and non-communicable conditions that result in anomalous or destructive brain lesions. The appearance of the fetal brain also changes significantly through gestation as different structures mature and the cerebral cortex in particular increases in size and complexity. Therefore, obstetrical imagers and maternal fetal medicine physicians need to be aware of the expected evolving appearances of the healthy fetal brain as the fetus advances in gestation. Often when fetal CNS pathology is detected or anticipated during pregnancy, there is understandably significant parental anxiety regarding the long-term implications of their child's neurodevelopmental prognosis. In these instances, Maternal Fetal Medicine specialists often collaborate with Pediatric Neurologists in the antenatal period regarding diagnoses that anticipate neonatal or later childhood neurologic sequelae. Potential adverse outcomes are discussed with prospective parents to be integrated into choices based on shared decisions.
    Keywords:  Fetal neuroimaging; Interdisciplinary fetal neurology consultations; Maternal-fetal medicine surveillance; Parental counselling
    DOI:  https://doi.org/10.1016/j.siny.2024.101555
  17. Mol Ther Methods Clin Dev. 2024 Dec 12. 32(4): 101357
    Advances in AAV-mediated gene replacement therapy for pediatric monogenic neurological disorders.
    Livia Zhou, Yafeng Wang, Yiran Xu, Yaodong Zhang, Changlian Zhu.
      Pediatric monogenetic diseases encompass a spectrum of debilitating neurological disorders that affect infants and children, often resulting in profound cognitive and motor impairments. Gene replacement therapy holds immense promise in addressing the underlying genetic defects responsible for these conditions. Adeno-associated virus (AAV) vectors have emerged as a leading platform for delivering therapeutic genes due to their safety profile and ability to transduce various cell types, including neurons. This review highlights recent advancements in AAV-mediated gene replacement therapy for pediatric monogenetic diseases, focusing on key preclinical and clinical studies. We discuss various strategies to enhance transduction efficiency, target specificity, and safety. Furthermore, we explore challenges such as immune responses, along with innovative approaches to overcome these obstacles. Moreover, we examine the clinical outcomes and safety profiles of AAV-based gene therapies in pediatric patients, providing insights into the feasibility and efficacy of these interventions. Finally, we discuss future directions and potential avenues for further research to optimize the therapeutic potential of AAV-delivered gene replacement therapy for pediatric encephalopathies, ultimately aiming to improve the quality of life for affected individuals and their families.
    Keywords:  AAV; gene therapy; monogenetic diseases; neurology; pediatrics
    DOI:  https://doi.org/10.1016/j.omtm.2024.101357
  18. J Clin Endocrinol Metab. 2024 Nov 22. pii: dgae815. [Epub ahead of print]
    Disordered electron transfer: New forms of defective steroidogenesis and mitochondriopathy.
    Walter L Miller, Amit V Pandey, Christa E Flück.
      Most disorders of steroidogenesis, such as forms of congenital adrenal hyperplasia (CAH) are caused by mutations in genes encoding the steroidogenic enzymes and are often recognized clinically by cortisol deficiency, hyper- or hypo-androgenism, and/or altered mineralocorticoid function. Most steroidogenic enzymes are forms of cytochrome P450. Most P450s, including several steroidogenic enzymes, are microsomal, requiring electron donation by P450 oxidoreductase (POR); but several steroidogenic enzymes are mitochondrial P450s, requiring electron donation via ferredoxin reductase (FDXR) and ferredoxin (FDX). POR deficiency is a rare but well-described form of CAH characterized by impaired activity of 21-hydroxylase (P450c21, CYP21A2) and 17-hydroxylase/17,20-lyase (P450c17, CYP17A1); more severely affected individuals also have the Antley-Bixler skeletal malformation syndrome and disordered genital development in both sexes, and hence is easily recognized. The 17,20-lyase activity of P450c17 requires both POR and cytochrome b5 (b5), which promote electron transfer. Mutations of POR, b5, or P450c17 can cause selective 17,20-lyase deficiency. In addition to providing electrons to mitochondrial P450s, FDX and FDXR are required for the synthesis of iron-sulfur clusters, which are used by many enzymes. Recent work has identified FDXR mutations in patients with visual impairment, optic atrophy, neuropathic hearing loss and developmental delay, resembling the global neurologic disorders seen with mitochondrial diseases. Many of these patients have had life-threatening events or deadly infections, often without an apparent triggering event. Adrenal insufficiency has been predicted in such individuals but has only been documented recently. Neurologists, neonatologists and geneticists should seek endocrine assistance in evaluating and treating patients with mutations in FDXR.
    Keywords:  FDXR-related mitochondriopathy; adrenal; congenital adrenal hyperplasia; cytochrome P450; electron transfer; ferredoxin; ferredoxin reductase; mitochondria; mitochondrial neuropathy; oxidoreductase
    DOI:  https://doi.org/10.1210/clinem/dgae815
  19. Elife. 2024 Nov 22. pii: RP87083. [Epub ahead of print]12
    Switching of RNA splicing regulators in immature neuroblasts during adult neurogenesis.
    Corentin Bernou, Marc-André Mouthon, Mathieu Daynac, Thierry Kortulewski, Benjamin Demaille, Vilma Barroca, Sebastien Couillard-Despres, Nathalie Dechamps, Véronique Ménard, Léa Bellenger, Christophe Antoniewski, Alexandra Déborah Chicheportiche, François Dominique Boussin.
      The lateral wall of the mouse subventricular zone harbors neural stem cells (NSC, B cells) which generate proliferating transient-amplifying progenitors (TAP, C cells) that ultimately give rise to neuroblasts (NB, A cells). Molecular profiling at the single-cell level struggles to distinguish these different cell types. Here, we combined transcriptome analyses of FACS-sorted cells and single-cell RNAseq to demonstrate the existence of an abundant, clonogenic and multipotent population of immature neuroblasts (iNB cells) at the transition between TAP and migrating NB (mNB). iNB are reversibly engaged in neuronal differentiation. Indeed, they keep molecular features of both undifferentiated progenitors, plasticity and unexpected regenerative properties. Strikingly, they undergo important progressive molecular switches, including changes in the expression of splicing regulators leading to their differentiation in mNB subdividing them into two subtypes, iNB1 and iNB2. Due to their plastic properties, iNB could represent a new target for regenerative therapy of brain damage.
    Keywords:  Subventricular zone; adult neurogenesis; immature neuroblasts; mouse; regenerative medicine; stem cells; transcriptomic analysis
    DOI:  https://doi.org/10.7554/eLife.87083
  20. Neuropharmacology. 2024 Nov 16. pii: S0028-3908(24)00386-1. [Epub ahead of print]264 110217
    Mitochondrial DAMPs: Key mediators in neuroinflammation and neurodegenerative disease pathogenesis.
    Haihan Yu, Kaidi Ren, Yage Jin, Li Zhang, Hui Liu, Zhen Huang, Ziheng Zhang, Xing Chen, Yang Yang, Ziqing Wei.
      Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are increasingly linked to mitochondrial dysfunction and neuroinflammation. Central to this link are mitochondrial damage-associated molecular patterns (mtDAMPs), including mitochondrial DNA, ATP, and reactive oxygen species, released during mitochondrial stress or damage. These mtDAMPs activate inflammatory pathways, such as the NLRP3 inflammasome and cGAS-STING, contributing to the progression of neurodegenerative diseases. This review delves into the mechanisms by which mtDAMPs drive neuroinflammation and discusses potential therapeutic strategies targeting these pathways to mitigate neurodegeneration. Additionally, it explores the cross-talk between mitochondria and the immune system, highlighting the complex interplay that exacerbates neuronal damage. Understanding the role of mtDAMPs could pave the way for novel treatments aimed at modulating neuroinflammation and slowing disease progression, ultimately improving patient outcome.
    Keywords:  Mitochondrial DNA; Mitochondrial damage-associated molecular patterns (mtDAMPs); NLRP3 inflammasome; Neurodegenerative diseases; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.neuropharm.2024.110217
  21. Nat Commun. 2024 Nov 16. 15(1): 9945
    NOTCH1 mitochondria localization during heart development promotes mitochondrial metabolism and the endothelial-to-mesenchymal transition in mice.
    Jie Wang, Rui Zhao, Sha Xu, Xiang-Yu Zhou, Ke Cai, Yu-Ling Chen, Ze-Yu Zhou, Xin Sun, Yan Shi, Feng Wang, Yong-Hao Gui, Hui Tao, Jian-Yuan Zhao.
      Notch signaling activation drives an endothelial-to-mesenchymal transition (EndMT) critical for heart development, although evidence suggests that the reprogramming of endothelial cell metabolism can regulate endothelial function independent of canonical cell signaling. Herein, we investigated the crosstalk between Notch signaling and metabolic reprogramming in the EndMT process. Biochemically, we find that the NOTCH1 intracellular domain (NICD1) localizes to endothelial cell mitochondria, where it interacts with and activates the complex to enhance mitochondrial metabolism. Targeting NICD1 to mitochondria induces more EndMT compared with wild-type NICD1, and small molecule activation of PDH during pregnancy improves the phenotype in a mouse model of congenital heart defect. A NOTCH1 mutation observed in non-syndromic tetralogy of Fallot patients decreases NICD1 mitochondrial localization and subsequent PDH activity in heart tissues. Altogether, our findings demonstrate NICD1 enrichment in mitochondria of the developing mouse heart, which induces EndMT by activating PDH and subsequently improving mitochondrial metabolism.
    DOI:  https://doi.org/10.1038/s41467-024-54407-7
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