Small molecules restore mutant mitochondrial DNA polymerase activity

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Abstract Mammalian mitochondrial DNA (mtDNA) is replicated by polymerase γ (POLγ), a heterotrimeric complex consisting of catalytic POLγA subunit and two accessory POLγB subunits 1 . More than 300 mutations in POLG , the gene encoding subunit, have been linked to severe, progressive conditions with high rates morbidity mortality, for which no treatment exists 2 Here we report on discovery characterization PZL-A, first-in-class small-molecule activator mtDNA synthesis that capable restoring function most common mutant variants POLγ. PZL-A binds an allosteric site at interface between proximal region unaffected nearly all disease-causing mutations. The compound restores wild-type-like activity forms POLγ vitro activates cells from paediatric patients lethal disease, thereby enhancing biogenesis oxidative phosphorylation machinery cellular respiration. Our work demonstrates small molecule can restore polymerases, offering promising avenue treating disorders other severe depletion mtDNA.

Language: Английский

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Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias

Nature Metabolism, Journal Year: 2019, Volume and Issue: 1(10), P. 958 - 965

Published: Oct. 7, 2019

Language: Английский

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Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(23), P. 15166 - 15166

Published: Dec. 2, 2022

The kidney is a mitochondria-rich organ, and diseases are recognized as mitochondria-related pathologies. Intact mitochondrial DNA (mtDNA) maintains normal function. Mitochondrial dysfunction caused by mtDNA damage, including impaired replication, mutation, leakage, methylation, involved in the progression of diseases. Herein, we review roles damage different setting diseases, acute injury (AKI) chronic disease (CKD). In variety closely associated with loss level peripheral serum urine also reflects status injury. Alleviating can promote recovery function exogenous drug treatment thus reduce short, conclude that may serve novel biomarker for assessing causes renal dysfunction, which provides new theoretical basis mtDNA-targeted intervention therapeutic option

Language: Английский

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A steric gate prevents mutagenic dATP incorporation opposite 8‐oxo‐deoxyguanosine in mitochondrial DNA polymerases

FEBS Journal, Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

Reactive oxygen species (ROS) generate DNA lesions that alter genome integrity. Among those lesions, 7,8‐dihydro‐8‐oxo‐2′‐deoxyguanosine (8‐oxodG) is particularly mutagenic. 8‐oxodG efficiently incorporates deoxycytidine monophosphate (dCMP) and deoxyadenosine (dAMP) via base pairing mediated by its anti syn conformations, respectively. In family‐A polymerases (DNAPs), the amino acids responsible for modulating dCMP or dAMP incorporation across are located in a determined structural position. Those residues conserved tyrosine at N terminus of α‐helix O nonconserved residue six after this tyrosine. yeast mitochondrial DNAP (DNA‐directed polymerase gamma MIP1 [Mip1]), correspond to Y757 F763. We hypothesized phenyl group F763 impinges on conformation 8‐oxodG, therefore reducing misincorporation. Here, we measured using wild‐type Mip1 mutants. Our data suggest both universally assemble steric gate obtrudes 8‐oxodG( ) conformation. As human orthologue Mip1, (HsPolγ) γ, also harbors phenylalanine corresponding position Mip1‐F763, mechanism might similarly be controlling HsPolγ's fidelity when tolerating lesions.

Language: Английский

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Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of RRM2B mtDNA depletion syndrome

Human Molecular Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: April 11, 2025

Abstract Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are rare, clinically heterogeneous mitochondrial disorders resulting from nuclear variants in genes of the replication or maintenance machinery. Supplementation with pyrimidine deoxynucleosides have been beneficial patients and mice TK2-related MDDS, however, it has not systematically explored other forms MDDS. To investigate effect deoxynucleoside supplementation mitigating disease due to pathogenic RRM2B variants, we generated a novel zebrafish knock-out model this studied different combinations deoxynucleosides. Zebrafish larvae carrying homozygous nonsense mutation rrm2b present impaired movement, reduced mtDNA copy number elevated lactate. combination was performed, increased numbers when supplemented two purine (dGuo dAdo), while had no even further compromised zebrafish. In parallel number, detected improved movement reduction lactate rrm2b−/− fish, confirming on whole organism. This treatment did result any deleterious wild type heterozygous fish. Our data suggest that may be should investigated RRM2B-related disease, adding growing evidence is valid therapeutic approach which can trialled for treating wider range genetic

Language: Английский

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Clinical, pathological and genetic spectrum in 89 cases of mitochondrial progressive external ophthalmoplegia

Journal of Medical Genetics, Journal Year: 2020, Volume and Issue: 57(9), P. 643 - 646

Published: March 11, 2020

Background Mitochondrial progressive external ophthalmoplegia (PEO) encompasses a broad spectrum of clinical and genetic disorders. We describe the phenotypic subtypes PEO its correlation with molecular defects propose diagnostic algorithm. Methods Retrospective analysis clinical, pathological features 89 cases. Results Three main phenotypes were found: ‘pure PEO’ (42%), consisting isolated palpebral ptosis ophthalmoparesis; Kearns-Sayre syndrome (10%); ‘PEO plus’, which associates extraocular symptoms, distinguishing following subtypes: : myopathic (33%), bulbar (12%) others (3%). Muscle biopsy was most accurate test, showing mitochondrial changes in 95%. Genetic diagnosis achieved 96% patients. Single large-scale DNA (mtDNA) deletion frequent finding (63%), followed by multiple mtDNA deletions (26%) due to mutations TWNK (n=8), POLG (n=7), TK2 (n=6) or RRM2B (n=2) genes, point (7%). new likely pathogenic identified MT-TN genes. Conclusions Phenotype–genotype correlations cannot be brought PEO. should first step flow when aetiology is suspected since it also enables study rearrangements. If no are identified, whole sequencing performed.

Language: Английский

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Decoding the mitochondria without a code: mechanistic insights into mitochondrial DNA depletion syndromes

Journal of Biosciences, Journal Year: 2024, Volume and Issue: 49(1)

Published: Feb. 19, 2024

Language: Английский

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Nucleoside supplements as treatments for mitochondrial DNA depletion syndrome

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: April 2, 2024

Introduction: In mitochondrial DNA (mtDNA) depletion syndrome (MDS), patients cannot maintain sufficient mtDNA for their energy needs. MDS presentations range from infantile encephalopathy with hepatopathy (Alpers syndrome) to adult chronic progressive external ophthalmoplegia. Most are caused by nucleotide imbalance or defects in the replisome. There is currently no curative treatment available. Nucleoside therapy a promising experimental TK2 deficiency, where supplemented exogenous deoxypyrimidines. We aimed explore benefits of nucleoside supplementation POLG and TWNK deficient fibroblasts. Methods: used high-content fluorescence microscopy software-based image analysis assay content membrane potential quantitatively, using vital dyes PicoGreen MitoTracker Red CMXRos respectively. tested effect 15 combinations (A, T, G, C, AT, AC, AG, CT, CG, GT, ATC, ATG, AGC, TGC, ATGC) deoxynucleoside supplements on fibroblasts derived four (POLG1, POLG2, DGUOK, TWNK) both replicating (10% dialysed FCS) quiescent (0.1% state. qPCR measure non-supplemented following 20 µM ddC after 14- 21-day recovery Results: treatments at 200 that significantly increased also reduced number cells remaining culture 7 days treatment, as well potential. These toxic effects were abolished reducing concentration nucleosides 50 µM. POLG1 combination ATGC most non-replicating cells. rate ddC. Conclusion: High-content imaging enabled us link copy key read-outs linked patient wellbeing. Elevated G but severely impaired fibroblast growth, potentially inhibiting purine synthesis and/or causing replication stress. Combinations ATGC, TC, benefited growth harbouring mutations. combinations, one which reflects commercially available preparation, could be explored further patients.

Language: Английский

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Therapy Prospects for Mitochondrial DNA Maintenance Disorders

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(12), P. 6447 - 6447

Published: June 16, 2021

Mitochondrial DNA depletion and multiple deletions syndromes (MDDS) constitute a group of mitochondrial diseases defined by dysfunctional (mtDNA) replication maintenance. As is the case for many other diseases, options treatment these disorders are rather limited today. Some aggressive treatments such as liver transplantation or allogeneic stem cell among few available patients with some forms MDDS. However, in recent years, significant advances our knowledge biochemical pathomechanisms accounting mtDNA have been achieved, which has opened new prospects often fatal diseases. Current strategies under investigation to treat MDDS range from small molecule substrate enhancement approaches more complex treatments, lentiviral adenoassociated vector-mediated gene therapy. experimental therapies already reached clinical phase very promising results, however, they hampered fact that all rare so patient recruitment potential trials limited.

Language: Английский

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Mitochondrial DNA maintenance defects: potential therapeutic strategies

Molecular Genetics and Metabolism, Journal Year: 2022, Volume and Issue: 137(1-2), P. 40 - 48

Published: July 6, 2022

Language: Английский

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