Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency

Granat, Lucy; Knorr, Debbra Y.; Ranson, Daniel; Hamer, Emma; Chakrabarty, Ram Prosad; Mattedi, Francesca; Fort-Aznar, Laura; Hirth, Frank; Sweeney, Sean T.; Vagnoni, Alessio; Chandel, Navdeep S.; Bateman, J.E.

doi:10.1371/journal.pgen.1010793

Cited by 5 publications

(20 citation statements)

References 77 publications

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“…Subunits of the 26S proteasome (e.g. Prosalpha4, Prosalpha5, Prosbeta7, ) were strongly enriched in the ND-75 KDweak downregulated DEGs, whereas no 26S proteasome subunits were downregulated in ND-75 KDstrong flies (Figure 4C-E Complex I deficiency causes profound alterations in brain metabolism (McElroy et al, 2020;van de Wal et al, 2022;Granat et al, 2023). In keeping with this, our transcriptomic analysis showed ND-75 knockdown results in altered expression of metabolic genes such as Ldh.…”

Section: Weak and Strong Nd-75 Knockdown Have Different Effects On Tr...supporting

confidence: 76%

“…For behavioural assays with ND-75 KDstrong flies, vials were placed on their sides during eclosion to prevent flies from becoming stuck in the food. Open-field locomotor activity, seizure, lifespan and CApillary FEeder assay (CAFE) analysis was performed as in (Granat et al, 2023).…”

Section: Behavioural Analysismentioning

confidence: 99%

“…Complex I assay was performed as in (Granat et al, 2023) Immunofluorescence and imaging Images were taken using a Nikon A1R confocal microscope or a Nikon Vt-iSIM super resolution microscope with NIS Elements software. Confocal imaging and quantification was performed as in (Granat et al, 2023). A Vt-iSIM super resolution microscope (Nikon) was used to capture mitoGFP expression as in (Granat et al, 2023).…”

Section: Mitochondrial Nadh Dehydrogenase (Complex I) Assaymentioning

confidence: 99%

“…Metabolomics was performed as in (Granat et al, 2023). Metabolomic data were analysed using MetaboAnalyst 5.0 (Chong et al, 2018).…”

Section: Metabolomic Analysismentioning

confidence: 99%

“…However, none of these models have recapitulated the phenotypic heterogeneity observed within mitochondrial disease caused by mutations in the same gene. We recently generated a Drosophila model of complex I deficiency using knockdown of the complex I subunit NDUFS1 (ND-75) in Drosophila (Granat et al, 2023). Knockdown of ND-75 in this model is highly efficient and results in severe neurological symptoms and very early death, reflecting severe complex I deficiency.…”

Section: Introductionmentioning

confidence: 99%

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ADrosophilamodel of mitochondrial disease phenotypic heterogeneity

Granat,

Knorr,

Ranson

et al. 2023

Preprint

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Mutations in genes that affect mitochondrial function cause primary mitochondrial diseases. Mitochondrial diseases are highly heterogeneous and even patients with the same mitochondrial disease can exhibit broad phenotypic heterogeneity, which is poorly understood. Mutations in subunits of mitochondrial respiratory complex I cause complex I deficiency, which can result in severe neurological symptoms and death in infancy. However, some complex I deficiency patients present with much milder symptoms. The most common nuclear gene mutated in complex I deficiency is the highly conserved core subunit NDUFS1. To model the phenotypic heterogeneity in complex I deficiency we used RNAi lines targeting theDrosophilaNDUFS1 homolog ND-75 with different efficiencies. Strong knockdown of ND-75 inDrosophilaneurons resulted in severe behavioural phenotypes, reduced lifespan, altered mitochondrial morphology, reduced endoplasmic reticulum (ER)-mitochondria contacts and activation of the unfolded protein response (UPR). By contrast, weak ND-75 knockdown caused much milder behavioural phenotypes and changes in mitochondrial morphology. Moreover, weak ND-75 did not alter ER-mitochondria contacts or activate the UPR. Weak and strong ND-75 knockdown resulted in overlapping but distinct transcriptional responses in the brain, with weak knockdown specifically affecting proteosome activity and immune response genes. Metabolism was also differentially affected by weak and strong ND-75 knockdown including gamma-aminobutyric acid (GABA) levels, which may contribute to neuronal dysfunction in ND-75 knockdown flies. Several metabolic processes were only affected by strong ND-75 knockdown including the pentose phosphate pathway and the metabolite 2-hydroxyglutarate (2-HG), suggesting 2-HG as a candidate biomarker of severe neurological mitochondrial disease. Thus, ourDrosophilamodel provides the means to dissect the mechanisms underlying phenotypic heterogeneity in mitochondrial disease.

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Section: Weak and Strong Nd-75 Knockdown Have Different Effects On Tr...supporting

confidence: 76%

Section: Behavioural Analysismentioning

confidence: 99%

Section: Mitochondrial Nadh Dehydrogenase (Complex I) Assaymentioning

confidence: 99%

“…Metabolomics was performed as in (Granat et al, 2023). Metabolomic data were analysed using MetaboAnalyst 5.0 (Chong et al, 2018).…”

Section: Metabolomic Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

ADrosophilamodel of mitochondrial disease phenotypic heterogeneity

Granat,

Knorr,

Ranson

et al. 2023

Preprint

Self Cite

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Alternative NADH dehydrogenase: A complex I backup, a drug target, and a tool for mitochondrial gene therapy

Gospodaryov

2025

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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A Drosophila model of mitochondrial disease phenotypic heterogeneity

Granat,

Knorr,

Ranson

et al. 2024

Biology Open

Self Cite

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Mutations in genes that affect mitochondrial function cause primary mitochondrial diseases. Mitochondrial diseases are highly heterogeneous and even patients with the same mitochondrial disease can exhibit broad phenotypic heterogeneity, which is poorly understood. Mutations in subunits of mitochondrial respiratory complex I cause complex I deficiency, which can result in severe neurological symptoms and death in infancy. However, some complex I deficiency patients present with much milder symptoms. The most common nuclear gene mutated in complex I deficiency is the highly conserved core subunit NDUFS1. To model the phenotypic heterogeneity in complex I deficiency we used RNAi lines targeting the Drosophila NDUFS1 homolog ND-75 with different efficiencies. Strong knockdown of ND-75 in Drosophila neurons resulted in severe behavioural phenotypes, reduced lifespan, altered mitochondrial morphology, reduced endoplasmic reticulum (ER)-mitochondria contacts and activation of the unfolded protein response (UPR). By contrast, weak ND-75 knockdown caused much milder behavioural phenotypes and changes in mitochondrial morphology. Moreover, weak ND-75 did not alter ER-mitochondria contacts or activate the UPR. Weak and strong ND-75 knockdown resulted in overlapping but distinct transcriptional responses in the brain, with weak knockdown specifically affecting proteosome activity and immune response genes. Metabolism was also differentially affected by weak and strong ND-75 knockdown including gamma-aminobutyric acid (GABA) levels, which may contribute to neuronal dysfunction in ND-75 knockdown flies. Several metabolic processes were only affected by strong ND-75 knockdown including the pentose phosphate pathway and the metabolite 2-hydroxyglutarate (2-HG), suggesting 2-HG as a candidate biomarker of severe neurological mitochondrial disease. Thus, our Drosophila model provides the means to dissect the mechanisms underlying phenotypic heterogeneity in mitochondrial disease.

show abstract

Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency

Cited by 5 publications

References 77 publications

ADrosophilamodel of mitochondrial disease phenotypic heterogeneity

ADrosophilamodel of mitochondrial disease phenotypic heterogeneity

Alternative NADH dehydrogenase: A complex I backup, a drug target, and a tool for mitochondrial gene therapy

A Drosophila model of mitochondrial disease phenotypic heterogeneity

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