bims-curels 2024-11-17 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2024‒11‒17
nine papers selected by
Cure Mito Foundation

Leber Hereditary Optic Neuropathy With Significant Visual Recovery: An MT-ND6 Mutation in a Malay Patient.
Current global vitamin and cofactor prescribing practices for primary mitochondrial diseases: Results of a European reference network survey.
POLG p.A962T Mutation Leads to Neuronal Mitochondrial Dysfunction That is Restored After Mitochondrial Transplantation.
CRISPR-Cas9 mediated knockout of NDUFS4 in human iPSCs: A model for mitochondrial complex I deficiency.
Genetic landscape of primary mitochondrial diseases in children and adults using molecular genetics and genomic investigations of mitochondrial and nuclear genome.
Mitochondrial disorders are associated with morphological neuromuscular junction defects.
Mitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli.
Structural basis of 3'-tRNA maturation by the human mitochondrial RNase Z complex.
Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.

Cureus. 2024 Oct;16(10): e71210

Leber Hereditary Optic Neuropathy With Significant Visual Recovery: An MT-ND6 Mutation in a Malay Patient.

Muhammad Arif Ozir, Mohammad Hudzaifah Nordin, Syaratul Emma Hashim, Sumaiyah Adzahar, Muhammad Aizuddin Ahmad, Kwang Sheng Ng, Wan-Hazabbah Wan Hitam.

  Leber hereditary optic neuropathy (LHON) is a rare maternally inherited mitochondrial disorder that predominantly affects young men, leading to optic nerve degeneration and subsequent vision loss. The rarity of LHON and its clinical similarity to optic neuritis complicates diagnosis, necessitating genetic testing to confirm specific point mutations and predict visual outcomes. We report a rare case of an 18-year-old Malay male with m.14484T>C/MT-ND6 mutation of LHON, who demonstrated remarkable spontaneous visual recovery over a three-year follow-up period. This report highlights the pivotal role of genetic testing in diagnosing LHON, explores the variability in visual outcomes associated with different mutations, and underscores the potential for spontaneous recovery in specific mutation variants. Early diagnosis, genetic counseling, and supportive management are critical for optimizing outcomes and improving quality of life.

Keywords:  idebenone; leber hereditary optic neuropathy; mitochondrial disease; optic neuritis; optic neuropathy

DOI:  https://doi.org/10.7759/cureus.71210
J Inherit Metab Dis. 2024 Nov 11.

Current global vitamin and cofactor prescribing practices for primary mitochondrial diseases: Results of a European reference network survey.

MetabERN PM‐MD Consortium authors

  Primary mitochondrial diseases (PMD) account for a group of approximately 400 different genetic disorders with diverse clinical presentations and pathomechanisms. Although each individual disorder is rare, collectively they represent one of the largest groups in the field of inherited metabolic disorders. The complexity of PMD results in a continued lack of therapeutic options, necessitating a predominantly symptomatic treatment approach for affected patients. While a subset of diseases responds exceptionally well to treatment with specific vitamins or cofactors, for most PMD systematic reviews were not able to show significant benefit. This is in discrepancy to their continued frequent use among specialists. To gain further insight into the current clinical practice of vitamin and cofactor supplementation among clinicians treating children and adults affected by PMD, we conducted a worldwide cross-sectional questionnaire study exploring the choice of substances and the specific diseases where they are applied. To our knowledge, this is the first global study exploring this topic and featuring a high response rate from paediatricians. The vast majority (95%, 106/112) of responding specialists recommended the use of vitamins and cofactors, either in an agnostic approach irrespective of the specific PMD or directed to the treatment of specific diseases or phenotypes. Our study highlights significant regional and specialty-specific differences in supplementation practices. We provide some preliminary insights into specialist-based opinions regarding the use of vitamins and cofactors in PMD and highlight the need for more rigorous clinical and preclinical investigations and/or clear consensus statements.

Keywords:  cofactors; cross sectional study; inherited metabolic disease; primary mitochondrial disease; survey; treatment; vitamins

DOI:  https://doi.org/10.1002/jimd.12805
Physiol Res. 2024 Nov 15. 73(5): 801-808

POLG p.A962T Mutation Leads to Neuronal Mitochondrial Dysfunction That is Restored After Mitochondrial Transplantation.

W Hu, C Shi, H Guo, B Zhang.

Mutations in DNA polymerase gamma (POLG) are known as the predominant cause of inherited mitochondrial disorders. But how these POLG mutations disturb mitochondrial function remains to be determined. Furthermore, no effective therapy, to date, has been reported for POLG diseases. Using differentiated SH-SY5Y cells, a human neuronal model cell line, the current study investigated whether the novel POLG variant p.A962T impairs mitochondrial function. This involved quantifying mitochondrial DNA (mtDNA) content using PCR and assessing the expression levels of the subunits of complex IV (COXI-IV), a complex I subunit NDUFV1 and Cytochrome C (Cyto C) release using Western blotting. Activities of mitochondrial complex I, II, and IV were measured using colorimetric assays. Mitochondrial membrane potential (delta Psim) and ATP were evaluated using fluorescence assays and luminescent assays, respectively. In addition, we investigated whether mitochondrial transplantation (MT) using Pep-1-conjugated mitochondria could compensate for mitochondrial defects caused by the variant in cells carrying mutant POLG. The results of this study showed that POLG p.A962T mutation resulted in mitochondrial defects, including mitochondrial DNA (mtDNA) depletion, membrane potential (delta Psim) depolarization and adenosine triphosphate (ATP) reduction. Mechanistically, POLG mutation-caused mtDNA depletion led to the loss of mtDNA-encoded subunits of complex I and IV and thus compromised their activities. POLG p.A962T mutation is a pathogenic mutation leading to mitochondrial malfunction and mtDNA depletion in neurons. Cell-penetrating peptide Pep-1-mediated MT treatment compensated for mitochondrial defects induced by these POLG variants, suggesting the therapeutic application of this method in POLG diseases.
Biochim Biophys Acta Mol Basis Dis. 2024 Nov 13. pii: S0925-4439(24)00563-5. [Epub ahead of print] 167569

CRISPR-Cas9 mediated knockout of NDUFS4 in human iPSCs: A model for mitochondrial complex I deficiency.

Shivani Goolab, Karin Terburgh, Charl du Plessis, Janine Scholefield, Roan Louw.

  Mitochondrial diseases, often caused by defects in complex I (CI) of the oxidative phosphorylation system, currently lack curative treatments. Human-relevant, high-throughput drug screening platforms are crucial for the discovery of effective therapeutics, with induced pluripotent stem cells (iPSCs) emerging as a valuable technology for this purpose. Here, we present a novel iPSC model of NDUFS4-related CI deficiency that displays a strong metabolic phenotype in the pluripotent state. Human iPSCs were edited using CRISPR-Cas9 to target the NDUFS4 gene, generating isogenic NDUFS4 knockout (KO) cell lines. Sanger sequencing detected heterozygous biallelic deletions, whereas no indel mutations were found in isogenic control cells. Western blotting confirmed the absence of NDUFS4 protein in KO iPSCs and CI enzyme kinetics showed a ~56 % reduction in activity compared to isogenic controls. Comprehensive metabolomic profiling revealed a distinct metabolic phenotype in NDUFS4 KO iPSCs, predominantly associated with an elevated NADH/NAD+ ratio, consistent with alterations observed in other models of mitochondrial dysfunction. Additionally, β-lapachone, a recognized NAD+ modulator, alleviated reductive stress in KO iPSCs by modifying the redox state in both the cytosol and mitochondria. Although undifferentiated iPSCs cannot fully replicate the complex cellular dynamics of the disease seen in vivo, these findings highlight the utility of iPSCs in providing a relevant metabolic milieu that can facilitate early-stage, high-throughput exploration of therapeutic strategies for mitochondrial dysfunction.

Keywords:  CI deficiency; CRISPR-Cas9; Mitochondrial disease; iPSC

DOI:  https://doi.org/10.1016/j.bbadis.2024.167569
Orphanet J Rare Dis. 2024 Nov 12. 19(1): 424

Genetic landscape of primary mitochondrial diseases in children and adults using molecular genetics and genomic investigations of mitochondrial and nuclear genome.

Anastasia Ambrose, Shalini Bahl, Saloni Sharma, Dan Zhang, Clara Hung, Shailly Jain-Ghai, Alicia Chan, Saadet Mercimek-Andrews.

  BACKGROUND: Primary mitochondrial diseases (PMD) are one of the most common metabolic genetic disorders. They are due to pathogenic variants in the mitochondrial genome (mtDNA) or nuclear genome (nDNA) that impair mitochondrial function and/or structure. We hypothesize that there is overlap between PMD and other genetic diseases that are mimicking PMD. For this reason, we performed a retrospective cohort study.METHODS: All individuals with suspected PMD that underwent molecular genetic and genomic investigations were included. Individuals were grouped for comparison: (1) individuals with mtDNA-PMD; (2) individuals with nDNA-PMD; (3) individuals with other genetic diseases mimicking PMD (non-PMD); (4) individuals without a confirmed genetic diagnosis.
RESULTS: 297 individuals fulfilled inclusion criteria. The diagnostic yield of molecular genetics and genomic investigations was 31.3%, including 37% for clinical exome sequencing and 15.8% for mitochondrial genome sequencing. We identified 71 individuals with PMD (mtDNA n = 41, nDNA n = 30) and 22 individuals with non-PMD. Adults had higher percentage of mtDNA-PMD compared to children (p-value = 0.00123). There is a statistically significant phenotypic difference between children and adults with PMD.
CONCLUSION: We report a large cohort of individuals with PMD and the diagnostic yield of urine mitochondrial genome sequencing (16.1%). We think liver phenotype might be progressive and should be studied further in PMD. We showed a relationship between non-PMD genes and their indirect effects on mitochondrial machinery. Differentiation of PMD from non-PMD can be achieved using specific phenotypes as there was a statistically significant difference for muscular, cardiac, and ophthalmologic phenotypes, seizures, hearing loss, peripheral neuropathy in PMD group compared to non-PMD group.

Keywords:  Exome sequencing; Mitochondrial genome sequencing; Primary mitochondrial diseases

DOI:  https://doi.org/10.1186/s13023-024-03437-x
Neuromuscul Disord. 2024 Oct 25. pii: S0960-8966(24)01731-0. [Epub ahead of print]45 105235

Mitochondrial disorders are associated with morphological neuromuscular junction defects.

Lola E R Lessard, Emmanuelle Girard, Nathalie Streichenberger, Philippe Petiot, Cécile Acquaviva, Cécile Pagan, Peter Mulligan, Françoise Bouhour, Laurent Schaeffer, Arnaud Jacquier.

  We aimed to evaluate whether inherited mitochondrial dysfunction is associated with neuromuscular junction remodeling in patients with mitochondrial disorders. Muscle biopsies from 15 patients with mitochondrial disorders and 10 control patients were analyzed through immunostaining for various neuromuscular junction components. The patient group, with a mean age of 49.9 years, exhibited various mitochondrial disorders including chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. Patients with mitochondrial disorders had a high percentage of remodeled (p= 0.0001), neoformed (p= 0.0049) and dilated (p= 0.016) endplates. There was a trend toward an increased proportion of neuromuscular junctions with terminal Schwann cell extension in these patients (p= 0.052). No significant difference was found in myofiber diameter between the groups. The observed neuromuscular junction defects varied widely across different mitochondrial disorder phenotypes and were present even without accompanying muscle weakness or neuropathy. This suggest that mitochondrial disorders are associated with a primary NMJ remodeling independent of muscle structural damage. Pathomechanisms underpinning this remodeling of the neuromuscular junction, as well as clinical factors predictive of this remodeling, remain to be fully characterized.

Keywords:  Confocal microscopy; Denervation; Fatigability; Ptosis; Reinnervation; Remodeling

DOI:  https://doi.org/10.1016/j.nmd.2024.105235
Sci Rep. 2024 11 08. 14(1): 27182

Mitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli.

Lena Wischhof, Amal John Mathew, Lorenzo Bonaguro, Marc Beyer, Dan Ehninger, Pierluigi Nicotera, Daniele Bano.

  Inhibition of the mitochondrial oxidative phosphorylation (OXPHOS) system can lead to metabolic disorders and neurodegenerative diseases. In primary mitochondrial disorders, reactive astrocytes often accompany neuronal degeneration and may contribute to neurotoxic inflammatory cascades that elicit brain lesions. The influence of mitochondria to astrocyte reactivity as well as the underlying molecular mechanisms remain elusive. Here we report that mitochondrial Complex I dysfunction promotes neural progenitor cell differentiation into astrocytes that are more responsive to neuroinflammatory stimuli. We show that the SWItch/Sucrose Non-Fermentable (SWI/SNF/BAF) chromatin remodeling complex takes part in the epigenetic regulation of astrocyte responsiveness, since its pharmacological inhibition abrogates the expression of inflammatory genes. Furthermore, we demonstrate that Complex I deficient human iPSC-derived astrocytes negatively influence neuronal physiology upon cytokine stimulation. Together, our data describe the SWI/SNF/BAF complex as a sensor of altered mitochondrial OXPHOS and a downstream epigenetic regulator of astrocyte-mediated neuroinflammation.

Keywords:  ATP-dependent chromatin remodeling SWI/SNF/BAF complex; Mitochondria; Reactive astrocytes

DOI:  https://doi.org/10.1038/s41598-024-78434-y
EMBO J. 2024 Nov 08.

Structural basis of 3'-tRNA maturation by the human mitochondrial RNase Z complex.

Genís Valentín Gesé, B Martin Hällberg.

  Maturation of human mitochondrial tRNA is essential for cellular energy production, yet the underlying mechanisms remain only partially understood. Here, we present several cryo-EM structures of the mitochondrial RNase Z complex (ELAC2/SDR5C1/TRMT10C) bound to different maturation states of mitochondrial tRNAHis, showing the molecular basis for tRNA-substrate selection and catalysis. Our structural insights provide a molecular rationale for the 5'-to-3' tRNA processing order in mitochondria, the 3'-CCA antideterminant effect, and the basis for sequence-independent recognition of mitochondrial tRNA substrates. Furthermore, our study links mutations in ELAC2 to clinically relevant mitochondrial diseases, offering a deeper understanding of the molecular defects contributing to these conditions.

Keywords:  Cryo-EM; ELAC2; Mitochondria; RNA Processing; RNase Z

DOI:  https://doi.org/10.1038/s44318-024-00297-w
Sci Adv. 2024 Nov 15. 10(46): eadp7423

Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.

Anupama Tiwari, Jongyun Myeong, Arsalan Hashemiaghdam, Marion I Stunault, Hao Zhang, Xiangfeng Niu, Marissa A Laramie, Jasmin Sponagel, Leah P Shriver, Gary J Patti, Vitaly A Klyachko, Ghazaleh Ashrafi.

Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep or circuit activity, posing major metabolic stress. Here, we demonstrate that the mammalian brain uses pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability, and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation, which, in turn, modulates mitochondrial pyruvate uptake. Our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in neurotransmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval-functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of neurotransmission in hippocampal terminals.

DOI: https://doi.org/10.1126/sciadv.adp7423