Double administration of self-complementary AAV9NDUFS4 prevents Leigh disease in Ndufs4−/− mice DOI Creative Commons
Samantha Corrà, Raffaele Cerutti,

Valeria Balmaceda

et al.

Brain, Journal Year: 2022, Volume and Issue: 145(10), P. 3405 - 3414

Published: July 11, 2022

Abstract Leigh disease, or subacute necrotizing encephalomyelopathy, a genetically heterogeneous condition consistently characterized by defective mitochondrial bioenergetics, is the most common oxidative-phosphorylation related disease in infancy. Both neurological signs and pathological lesions of are mimicked ablation mouse respiratory chain subunit Ndufs4−/−, which part of, crucial for, normal Complex I activity assembly, particularly brains both children mice. We previously conveyed human NDUFS4 gene to brain using either single-stranded adeno-associated viral 9 recombinant vectors PHP.B vector. these approaches significantly prolonged lifespan Ndufs4−/− model but extension survival was limited few weeks former approach, whereas latter applicable number strains, not primates. Here, we exploited recent development new, self-complementary vectors, transcription rate markedly increased compared with can be applied all mammals, including humans. Either single intra-vascular double intra-cerebro-ventricular injections were performed at post-natal Day 1. The first strategy ubiquitously product mice, doubling from 45 ≈100 days after birth, when mice developed rapidly progressive failure. However, double, contemporary intra-cerebroventricular administration self-complementary-adeno-associated healthy up months age. These well active euthanization, 6, 7, 8 age, investigate other organs post-mortem. Robust expression hNDUFS4 detected different cerebral areas preserving morphology restoring assembly. Our results warrant further investigation on translatability NDUFS4-based therapy prodromal phase eventually

Language: Английский

Inflammation and aging: signaling pathways and intervention therapies DOI Creative Commons
Xia Li, Chentao Li, Wanying Zhang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: June 8, 2023

Abstract Aging is characterized by systemic chronic inflammation, which accompanied cellular senescence, immunosenescence, organ dysfunction, and age-related diseases. Given the multidimensional complexity of aging, there an urgent need for a systematic organization inflammaging through dimensionality reduction. Factors secreted senescent cells, known as senescence-associated secretory phenotype (SASP), promote inflammation can induce senescence in normal cells. At same time, accelerates immune resulting weakened function inability to clear cells inflammatory factors, creates vicious cycle senescence. Persistently elevated levels organs such bone marrow, liver, lungs cannot be eliminated leading damage aging-related Therefore, has been recognized endogenous factor elimination could potential strategy anti-aging. Here we discuss at molecular, cellular, organ, disease levels, review current aging models, implications cutting-edge single cell technologies, well anti-aging strategies. Since preventing alleviating diseases improving overall quality life are ultimate goals research, our highlights critical features mechanisms along with latest developments future directions providing theoretical foundation novel practical

Language: Английский

Citations

524
Expert Panel Curation of 113 Primary Mitochondrial Disease Genes for the Leigh Syndrome Spectrum DOI Creative Commons
Elizabeth M. McCormick,

Kierstin Keller,

Julie P. Taylor

et al.

Annals of Neurology, Journal Year: 2023, Volume and Issue: 94(4), P. 696 - 712

Published: May 31, 2023

Primary mitochondrial diseases (PMDs) are heterogeneous disorders caused by inherited dysfunction. Classically defined neuropathologically as subacute necrotizing encephalomyelopathy, Leigh syndrome spectrum (LSS) is the most frequent manifestation of PMD in children, but may also present adults. A major challenge for accurate diagnosis LSS genomic medicine era establishing gene-disease relationships (GDRs) this with >100 monogenic causes across both nuclear and genomes.

Language: Английский

Citations

27
NDUFS4 regulates cristae remodeling in diabetic kidney disease DOI Creative Commons
Koki Mise,

Jianyin Long,

Daniel L. Galvan

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 4, 2024

Abstract The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, role nature impaired ETC in kidney diseases remains poorly understood. Here, we generate diabetic mice podocyte-specific overexpression Ndufs4, an accessory subunit complex I, as model investigate integrity disease (DKD). We find that conditional male genetic Ndufs4 exhibit significant improvements cristae morphology, dynamics, albuminuria. By coupling proximity labeling super-resolution imaging, also identify shaping protein STOML2 linking NDUFS4 improved morphology. Together, provide evidence on central regulator remodeling function podocytes. propose targeting represents promising approach slow progression DKD.

Language: Английский

Citations

12
Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4−/− mouse DOI Creative Commons
Zhan Yin, Ahmed-Noor A. Agip, Hannah R. Bridges

et al.

The EMBO Journal, Journal Year: 2024, Volume and Issue: 43(2), P. 225 - 249

Published: Jan. 2, 2024

Abstract Respiratory complex I (NADH:ubiquinone oxidoreductase) is essential for cellular energy production and NAD + homeostasis. Complex mutations cause neuromuscular, mitochondrial diseases, such as Leigh Syndrome, but their molecular-level consequences remain poorly understood. Here, we use a popular I-linked disease model, the ndufs4 −/− mouse, to define structural, biochemical, functional of absence subunit NDUFS4. Cryo-EM analyses from mouse hearts revealed loose association NADH-dehydrogenase module, discrete classes containing either assembly factor NDUFAF2 or NDUFS6. Subunit NDUFA12, which replaces its paralogue in mature I, absent all classes, compounding deletion NDUFS4 preventing maturation an NDUFS4-free enzyme. We propose that recruits module during complex. Taken together, findings provide new understanding model disease.

Language: Английский

Citations

9
The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence DOI Creative Commons
Allison R. Hanaford, Simon C. Johnson

Orphanet Journal of Rare Diseases, Journal Year: 2022, Volume and Issue: 17(1)

Published: Sept. 2, 2022

Genetic mitochondrial diseases represent a significant challenge to human health. These are extraordinarily heterogeneous in clinical presentation and genetic origin, often involve multi-system disease with severe progressive symptoms. Mitochondrial the most common cause of inherited metabolic disorders one causes neurologic diseases, yet no proven therapeutic strategies exist. The basic cell molecular mechanisms underlying pathogenesis have not been resolved, hampering efforts develop agents.

Language: Английский

Citations

32
Cannabidiol ameliorates mitochondrial disease via PPARγ activation in preclinical models DOI Creative Commons
Emma Puighermanal, Marta Luna‐Sánchez, Alejandro Gella

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Sept. 4, 2024

Language: Английский

Citations

7
Gene Therapy for Mitochondrial Diseases: Current Status and Future Perspective DOI Creative Commons
Alessia Di Donfrancesco, Giulia Massaro, Ivano Di Meo

et al.

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(6), P. 1287 - 1287

Published: June 17, 2022

Mitochondrial diseases (MDs) are a group of severe genetic disorders caused by mutations in the nuclear or mitochondrial genome encoding proteins involved oxidative phosphorylation (OXPHOS) system. MDs have wide range symptoms, ranging from organ-specific to multisystemic dysfunctions, with different clinical outcomes. The lack natural history information, limits currently available preclinical models, and phenotypic presentations seen MD patients all hampered development effective therapies. growing number pre-clinical trials over last decade has shown that gene therapy is viable precision medicine option for treating MD. However, several obstacles must be overcome, including vector design, targeted tissue tropism efficient delivery, transgene expression, immunotoxicity. This manuscript offers comprehensive overview state art MD, addressing main challenges, most feasible solutions, future perspectives field.

Language: Английский

Citations

27
Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice DOI Creative Commons
Gregory S. McElroy, Ram Prosad Chakrabarty, Karis B. D’Alessandro

et al.

Scientific Reports, Journal Year: 2022, Volume and Issue: 12(1)

Published: March 25, 2022

Abstract Aging in mammals leads to reduction genes encoding the 45-subunit mitochondrial electron transport chain complex I. It has been hypothesized that normal aging and age-related diseases such as Parkinson’s disease are part due modest decrease expression of I subunits. By contrast, diminishing lower organisms increases lifespan. Furthermore, metformin, a putative inhibitor, healthspan mice humans. In present study, we investigated whether loss one allele Ndufs2 , catalytic subunit I, impacts lifespan mice. Our results indicate hemizygous ( +/− ) show no overt impairment aging-related motor function, learning, tissue histology, organismal metabolism, or sensitivity metformin C57BL6/J background. Despite significant mRNA, do not demonstrate function. However, there detectable transcriptomic changes individual cell types tissues . data 50% decline mRNA core is neither beneficial nor detrimental healthspan.

Language: Английский

Citations

23
Targeting Mitochondrial Complex I Deficiency in MPP+/MPTP-induced Parkinson’s Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene DOI Creative Commons
Hongzhi Li, Jing Zhang, Yuqi Shen

et al.

Biological Procedures Online, Journal Year: 2024, Volume and Issue: 26(1)

Published: April 9, 2024

Abstract Background MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), original found in synthetic heroin, causes Parkinson’s disease (PD) human through its metabolite MPP + by inhibiting complex I of mitochondrial respiratory chain dopaminergic neurons. This study explored whether yeast internal NADH-quinone oxidoreductase (NDI1) has therapeutic effects MPTP- induced PD models functionally compensating for the impaired I. -treated SH-SY5Y cells and MPTP-treated mice were used as cell culture mouse respectively. The recombinant NDI1 lentivirus was transduced into cells, or adeno-associated virus (rAAV5- ) injected substantia nigra pars compacta (SNpc) mice. Results vitro showed prevented -induced change morphology decreased viability, coupling efficiency, I-dependent oxygen consumption, mitochondria-derived ATP. vivo revealed that rAAV- injection significantly improved motor ability exploration behavior MPTP-induced Accordingly, notably neuron survival, reduced inflammatory response, increased dopamine content striatum activity nigra. Conclusions compensates defective /MPTP-induced models, vastly alleviates toxic effect on Our may provide a basis gene therapy sporadic with caused MPTP-like substance.

Language: Английский

Citations

6
Challenges and opportunities to bridge translational to clinical research for personalized mitochondrial medicine DOI Creative Commons
Andrea Gropman, Martine Uittenbogaard, Anne Chiaramello

et al.

Neurotherapeutics, Journal Year: 2024, Volume and Issue: 21(1), P. e00311 - e00311

Published: Jan. 1, 2024

Mitochondrial disorders are a group of rare and heterogeneous genetic diseases characterized by dysfunctional mitochondria leading to deficient adenosine triphosphate synthesis chronic energy deficit in patients. The majority these patients exhibit wide range phenotypic manifestations targeting several organ systems, making their clinical diagnosis management challenging. Bridging translational research is crucial for improving the early prognosis intractable mitochondrial discovering novel therapeutic drug candidates modalities. This review provides current state testing disorders, discusses challenges opportunities converting basic discoveries into settings, explores most suited patient-centric approaches harness extraordinary heterogeneity among affected same primary disorder, describes outlook trials.

Language: Английский

Citations

5