Mutations in NDUFS1 Cause Metabolic Reprogramming and Disruption of the Electron Transfer

Ni, Yang; Hagras, Muhammad A.; Konstantopoulou, Vassiliki; Mayr, Johannes A.; Stuchebrukhov, Alexei A.; Meierhofer, David

doi:10.3390/cells8101149

Cited by 43 publications

(28 citation statements)

References 100 publications

(132 reference statements)

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“…Peptide desalting was performed according to the manufacturer’s instructions (Pierce C18 Tips, Thermo Scientific). LC-MS/MS was carried out by nanoflow reverse-phase liquid chromatography (Dionex Ultimate 3000, Thermo Scientific) coupled online to a Q-Exactive HF Orbitrap mass spectrometer (Thermo Scientific), as reported previously 43 . Briefly, the LC separation was performed using a PicoFrit analytical column (75 μm (ID) × 50 cm (length), tip ID of 15 µm; New Objectives) in-house-packed with 3-µm C18 resin (Reprosil-AQ Pur, Dr. Maisch).…”

Section: Methodsmentioning

confidence: 99%

Dnmt1 has de novo activity targeted to transposable elements

Haggerty

Kretzmer

Riemenschneider

et al. 2021

Nat Struct Mol Biol

115

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DNA methylation plays a critical role during development, particularly in repressing retrotransposons. The mammalian methylation landscape is dependent on the combined activities of the canonical maintenance enzyme Dnmt1 and the de novo Dnmts, 3a and 3b. Here, we demonstrate that Dnmt1 displays de novo methylation activity in vitro and in vivo with specific retrotransposon targeting. We used whole-genome bisulfite and long-read Nanopore sequencing in genetically engineered methylation-depleted mouse embryonic stem cells to provide an in-depth assessment and quantification of this activity. Utilizing additional knockout lines and molecular characterization, we show that the de novo methylation activity of Dnmt1 depends on Uhrf1, and its genomic recruitment overlaps with regions that enrich for Uhrf1, Trim28 and H3K9 trimethylation. Our data demonstrate that Dnmt1 can catalyze DNA methylation in both a de novo and maintenance context, especially at retrotransposons, where this mechanism may provide additional stability for long-term repression and epigenetic propagation throughout development.

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Section: Methodsmentioning

confidence: 99%

Dnmt1 has de novo activity targeted to transposable elements

Haggerty

Kretzmer

Riemenschneider

et al. 2021

Nat Struct Mol Biol

115

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“…The results of this study not only confirm the previous observations of the role of ANT in respirasome formation, it also provides new convincing data, never reported previously with significant physiological implications for cellular metabolism. The reliance on electron transfer and the respirasome as key regulators of cellular metabolism was further reported by Ni et al [7]. This study focused on the impact of specific mutations on two core subunits of complex I on metabolic reprogramming and disruption of electron transfer.…”

Section: Mitochondria In Healthmentioning

confidence: 80%

Mitochondria in Health and Diseases

Javadov

Kozlov

Camara

2020

Cells

144

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Mitochondria are subcellular organelles evolved by endosymbiosis of bacteria with eukaryotic cells characteristics. They are the main source of ATP in the cell and play a pivotal role in cell life and cell death. Mitochondria are engaged in the pathogenesis of human diseases and aging directly or indirectly through a broad range of signaling pathways. However, despite an increased interest in mitochondria over the past decades, the mechanisms of mitochondria-mediated cell/organ dysfunction in response to pathological stimuli remain unknown. The Special Issue, “Mitochondria in Health and Diseases,” organized by Cells includes 24 review and original articles that highlight the latest achievements in elucidating the role of mitochondria under physiological (healthy) conditions and, in various cell/animal models of human diseases and, in patients. Altogether, the Special Issue summarizes and discusses different aspects of mitochondrial metabolism and function that open new avenues in understanding mitochondrial biology.

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“…NDUFS1 is one of the so-called core subunits, which are conserved from bacteria to human, while NDUFS4 is one of the accessory subunits, which have been shown to vary between species [26]. NDUFS1 is essential for the enzymatic function, specifically for the electron transfer within CI [27] while NDUFS4 seems to be crucial for the assembly and stability of the complex [28]. Since cardiopulmonary failure is most often the underlying cause of mortality in patients with mitochondrial disorders, we characterized animals pharyngeal muscle functionality.…”

Section: Resultsmentioning

confidence: 99%

Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein inC. elegans

Maglioni

Schiavi

Melcher

et al. 2020

Preprint

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Complex I deficiency represents 30% of the pathogenetic causes of human mitochondrial associated diseases (HMAD), thus being the most frequent defect of mitochondrial energy metabolism. Therapeutic options for these devastating, life-threating disorders, which in most cases present with neurodevelopmental defects, do not exist, in part due to the scarcity of appropriate model systems to study them. Caenorhabditis elegans is a powerful, genetically tractable model organism widely used to investigate neuronal development and degeneration.Here, we generated new C. elegans models for HMAD, which closely recapitulated the human pathologies, and we focused on two complex I disease models associated with Leigh Syndrome, nuo-5/NDUFS1-and lpd-5/NDUFS4-depleted animals, which were exploited for a suppressor screening. We identified lutein, among a library of natural compounds, for its ability to rescue the developmental arrest and neuronal deficits in the two models. Specifically, we found that lutein exerts its beneficial activity through suppression of a synaptic defect we disclosed for the first time upon nuo-5/NDUFS1 depletion, thus pointing to possible novel therapeutic targets for the human disease. 2 Abbreviations

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Mutations in NDUFS1 Cause Metabolic Reprogramming and Disruption of the Electron Transfer

Cited by 43 publications

References 100 publications

Dnmt1 has de novo activity targeted to transposable elements

Dnmt1 has de novo activity targeted to transposable elements

Mitochondria in Health and Diseases

Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein inC. elegans

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