Metallothionein 1 Overexpression Does Not Protect Against Mitochondrial Disease Pathology in Ndufs4 Knockout Mice

Miller, Hayley Christy; Louw, R.; Mereis, Michelle; Venter, Gerda; Boshoff, J.; Mienie, Liesel; Reenen, Mari van; Venter, Marianne; Lindeque, Jeremie Zander; Dominguez-Martinez, Adan; Quintana, Albert; Westhuizen, Francois H. van der

doi:10.1007/s12035-020-02121-y

Cited by 9 publications

(6 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, Mt1 overexpression in Ndufs4 −/− -WB mice (confirmed in quadriceps muscle and brain) did not prevent protein oxidation, oxidative stress or inflammation and did not rescue the disease phenotype. 81 This is compatible with other antioxidant-based therapies (see above), which did not rescue disease onset and severity. Evidence was provided that overexpression of the MIM-fusion and cristae-shaping protein optic atrophy 1 (OPA1) normalized aberrant mitochondrial cristae morphology in the forebrain and cerebellum of Ndufs4 −/− -WB mice.…”

Section: Intervention Studies In Ndufs4 Mouse Modelssupporting

confidence: 81%

“… 77 From PD35 onwards the mice: (i) failed to maintain balance on a ledge; (ii) failed in a negative geotaxis test; (iii) displayed a decline in locomotor activity in the open field test; (iv) exhibited deteriorating muscle strength on the wire grip hang test; and (v) were unable to remain on a rotating rod as long as wild-type littermates. 72 , 77 , 81 Although we do not have information at the level of individual animals, the water intake of Ndufs4 −/− -WB mice is ∼50% of that of wild-type mice and further decreases around PD32-36 (A.Q., unpublished observation). However, it was reported that food consumption of Ndufs4 −/− -WB animals was within the normal range during day, night and fasting.…”

Section: The Ndufs4 Whole-body Knockout Mouse Modelmentioning

confidence: 99%

See 1 more Smart Citation

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Wal

Adjobo‐Hermans

Keijer

et al. 2021

Brain

Self Cite

View full text Add to dashboard Cite

Mitochondria are small cellular constituents that generate cellular energy (ATP) by oxidative phosphorylation (OXPHOS). Dysfunction of these organelles is linked to a heterogeneous group of multisystemic disorders, including diabetes, cancer, ageing-related pathologies and rare mitochondrial diseases (MDs). With respect to the latter, mutations in subunit-encoding genes and assembly factors of the first OXPHOS complex (CI) induce isolated CI deficiency and Leigh syndrome (LS). This syndrome is an early-onset, often fatal, encephalopathy with a variable clinical presentation and poor prognosis due to the lack of effective intervention strategies. Mutations in the nuclear DNA (nDNA)-encoded NDUFS4 gene, encoding the NADH: Ubiquinone oxidoreductase subunit S4 (NDUFS4) of CI induce “mitochondrial complex I deficiency, nuclear type 1” (MC1DN1) and LS in pediatric patients. A variety of (tissue-specific) Ndufs4 knockout mouse models were developed to study the LS pathomechanism and intervention testing. Here, we review and discuss the role of CI and NDUFS4 mutations in human MD, and review how the analysis of Ndufs4 knockout mouse models has generated new insights into the MC1ND1/LS pathomechanism and its therapeutic targeting.

show abstract

Section: Intervention Studies In Ndufs4 Mouse Modelssupporting

confidence: 81%

Section: The Ndufs4 Whole-body Knockout Mouse Modelmentioning

confidence: 99%

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Wal

Adjobo‐Hermans

Keijer

et al. 2021

Brain

Self Cite

View full text Add to dashboard Cite

show abstract

“…Ndufs4 KO mice present with a characteristic fatal encephalopathy in which neurodegeneration and neuroinflammation occur in specific brain regions. These two processes are mainly observed in the VN, OB, brainstem, cerebellum, and hippocampus (Johnson et al, 2013; Miller et al, 2020; Quintana et al, 2010; Shil et al, 2021). This neurodegenerative and neuroinflammatory process is the main cause of the Ndufs4 KO phenotype since brain‐specific NDUFS4 deficiency (using Nes‐Cre mice) results in an almost identical phenotype to that of systemic Ndufs4 KO (Quintana et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

Microglial response promotes neurodegeneration in the Ndufs4 KO mouse model of Leigh syndrome

Aguilar

Comes

Canal

et al. 2022

Glia

Self Cite

View full text Add to dashboard Cite

Leigh syndrome is a mitochondrial disease characterized by neurodegeneration, neuroinflammation, and early death. Mice lacking NDUFS4, a mitochondrial complex I subunit (Ndufs4 KO mice), have been established as a good animal model for studying human pathology associated with Leigh syndrome. As the disease progresses, there is an increase in neurodegeneration and neuroinflammation, thereby leading to deteriorating neurological symptoms, including motor deficits, breathing alterations, and eventually, death of the animal. However, despite the magnitude of neuroinflammation associated with brain lesions, the role of neuroinflammatory pathways and their main cellular components have not been addressed directly as relevant players in the disease pathology. Here, we investigate the role of microglial cells, the main immune cells of the CNS, in Leigh-like syndrome pathology, by pharmacologically depleting them using the colony-stimulating factor 1 receptor antagonist PLX3397. Microglial depletion extended lifespan and delayed motor symptoms in Ndufs4 KO mice, likely by preventing neuronal loss. Next, we investigated the role of the major cytokine interleukin-6 (IL-6) in the disease progression. IL-6 deficiency partially rescued breathing abnormalities and modulated gliosis but did not extend the lifespan or rescue motor decline in Ndufs4 KO mice. The present results show that microglial accumulation is pathogenic, in a process independent of IL-6, and hints toward a contributing role of neuroinflammation in the disease of Ndufs4 KO mice and potentially in patients with Leigh syndrome.

show abstract

“…Animals were group housed under temperature-(22 ± 1°C), humidity-(55 ± 10%) and light-controlled (12:12 hour light/dark cycle) conditions with standard laboratory chow (Rodent Breeder, #RM1845, LabChef, Nutritionhub) and water provided ad libitum. Samples were collected between P45-50 as this age range was selected to represent the late stage of LS, based on our previous survival curves and phenotypic analyses (Miller et al, 2021).…”

Section: Animals and Housingmentioning

confidence: 99%

Cross-comparison of systemic and tissue-specific metabolomes in a mouse model of Leigh syndrome

et al. 2021

Self Cite

View full text Add to dashboard Cite

IntroductionThe value of metabolomics in multi-systemic mitochondrial disease research has been increasingly recognized, with the ability to investigate a variety of biofluids and tissues considered a particular advantage. Although minimally invasive biofluids are the generally favored sample type, it remains unknown whether systemic metabolomes provide a clear reflection of tissue-specific metabolic alterations. Objectives Here we cross-compare urine and tissue-specific metabolomes in the Ndufs4 knockout mouse model of Leigh syndrome-a complex neurometabolic MD defined by progressive focal lesions in specific brain regions-to identify and evaluate the extent of common and unique metabolic alterations on a systemic and brain regional level. Methods Untargeted and semi-targeted multi-platform metabolomics were performed on urine, four brain regions, and two muscle types of Ndufs4 KO (n≥19) vs wildtype (n≥20) mice. Results Widespread alterations were evident in alanine, aspartate, glutamate, and arginine metabolism in Ndufs4 KO mice; while brain-region specific metabolic signatures include the accumulation of branched-chain amino acids, proline, and glycolytic intermediates. Furthermore, we describe a systemic dysregulation in one-carbon metabolism and the tricarboxylic acid cycle, which was not clearly reflected in the Ndufs4 KO brain. Conclusion Our results confirm the value of urinary metabolomics when evaluating MD-associated metabolites, while cautioning against mechanistic studies relying solely on systemic biofluids. KeywordsNdufs4 knockout mice • Brain regions • Metabolomics • Mitochondrial disease • Complex I deficiency • Leigh syndrome Abbreviations 1C One-carbon 3-MH 3-methylhistidine BCAA Branched-chain amino acids BBD γ-butyrobetaine dioxygenase BHMT Betaine-homocysteine methyltransferase CI Complex I CII Complex II CoA Coenzyme A DHAP Dihydroxyacetone phosphate ES Effect size ETFDH Electron-transferring-flavoprotein dehydrogenase * Roan Louw

show abstract

Metallothionein 1 Overexpression Does Not Protect Against Mitochondrial Disease Pathology in Ndufs4 Knockout Mice

Cited by 9 publications

References 99 publications

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Microglial response promotes neurodegeneration in the Ndufs4 KO mouse model of Leigh syndrome

Cross-comparison of systemic and tissue-specific metabolomes in a mouse model of Leigh syndrome

Contact Info

Product

Resources

About