A Drosophila model of mitochondrial disease phenotypic heterogeneity

Lucy Granat; Debbra Y. Knorr; Daniel C. Ranson; Ram Prosad Chakrabarty; Navdeep S. Chandel; Joseph M. Bateman

doi:10.1242/bio.060278

A Drosophila model of mitochondrial disease phenotypic heterogeneity

Lucy Granat, Debbra Y. Knorr, Daniel C. Ranson, Ram Prosad Chakrabarty, Navdeep S. Chandel, Joseph M. Bateman^*

^*Corresponding author for this work

Medicine, Pulmonary Division

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

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.

Original language	English (US)
Article number	bio060278
Journal	Biology Open
Volume	13
Issue number	2
DOIs	https://doi.org/10.1242/bio.060278
State	Published - Feb 2024

Funding

Alzheimer’s Research UK [ARUK-IRG2017A-2]; Medical Research Council [MR/ V013130/1, MR/N013700/1]; Northwestern University Pulmonary and Critical Care Department Cugell predoctoral fellowship. Open Access funding provided by King’s College London. Deposited in PMC for immediate release. Stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) and the Vienna Drosophila Resource Center were used in this study. We are grateful to the King’s College London Centre for ultrastructural imaging for technical assistance and the Wohl Cellular Imaging Centre for help with light microscopy. This work was funded by Alzheimer’s Research UK (ARUK-IRG2017A-2) and the MRC (MR/V013130/1) to J.M.B.; L.G. was supported by the UK Medical Research Council (MR/N013700/1) and King’s College London MRC Doctoral Training Partnership in Biomedical Sciences; R.P.C. was supported by a Northwestern University Pulmonary and Critical Care Department Cugell predoctoral fellowship. Alzheimer’s Research UK [ARUK-IRG2017A-2]; Medical Research Council [MR/ V013130/1, MR/N013700/1]; Northwestern University Pulmonary and Critical Care Department Cugell predoctoral fellowship. Open Access funding provided by King’s College London. Deposited in PMC for immediate release. Stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) and the Vienna Drosophila Resource Center were used in this study. We are grateful to the King’s College London Centre for ultrastructural imaging for technical assistance and the Wohl Cellular Imaging Centre for help with light microscopy. This work was funded by Alzheimer’s Research UK (ARUK-IRG2017A-2) and the MRC (MR/V013130/1) to J.M.B.; L.G. was supported by the UK Medical Research Council (MR/N013700/1) and King’s College London MRC Doctoral Training Partnership in Biomedical Sciences; R.P.C. was supported by a Northwestern University Pulmonary and Critical Care Department Cugell predoctoral fellowship.

Keywords

Complex I deficiency
Metabolism
Mitochondria
Phenotypic heterogeneity
Signalling

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences

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10.1242/bio.060278

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title = "A Drosophila model of mitochondrial disease phenotypic heterogeneity",

abstract = "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.",

keywords = "Complex I deficiency, Metabolism, Mitochondria, Phenotypic heterogeneity, Signalling",

author = "Lucy Granat and Knorr, {Debbra Y.} and Ranson, {Daniel C.} and Chakrabarty, {Ram Prosad} and Chandel, {Navdeep S.} and Bateman, {Joseph M.}",

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AU - Bateman, Joseph M.

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AB - 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.

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A Drosophila model of mitochondrial disease phenotypic heterogeneity

Abstract

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Keywords

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