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

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Abstract

Introduction

The 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.

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Data availability

The metabolomics data obtained in this study can be accessed at the Common Fund’s National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench (https://www.metabolomicsworkbench.org) where it has been assigned project IDs: PR000721 (Terburgh et al., 2019a), PR001003 (Terburgh et al., 2021b), and PR001187 (Terburgh et al., 2021c).

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

FDR:

False discovery rate

G3P:

Gycerol-3-phosphate

GC-TOF-MS:

Gas chromatography time-of-flight mass spectrometry

GLUT1:

Glucose transporter 1

HP:

Hydroxyphenyl

KO:

Knockout

LC-MS/MS:

Liquid chromatography-tandem mass spectrometry

LS:

Leigh syndrome

MD:

Mitochondrial disease

NAD(P)H:

Nicotinamide adenine dinucleotide (phosphate)

NAG:

N-acetyl glutamate

OXPHOS:

Oxidative phosphorylation

P:

Postnatal day

Q:

Ubiquinone

SAM:

S-adenosyl methionine

SCF:

Short chain fatty acids

TCA:

Tricarboxylic acid

WT:

Wild type

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Acknowledgements

We thank W. Horak and J. Coetzer for their assistance with the metabolomics analyses as well as K. Venter and A. Fick, from the Pre-Clinical Drug Development Platform (PCDDP, NWU, RSA), for their assistance regarding animal handling.

Funding

This work was supported by the National Research Foundation of South Africa (NRF, Grant No. 92736, 108146,111479 and 121368), the Technology Innovation Agency of the Department of Science and Technology of South Africa (TIA, Grant No. Metabol. 01), and the North-West University (NWU). Opinions expressed and conclusions arrived at, are those of the authors and are not necessarily to be attributed to the NRF, TIA or NWU.

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  1. Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University (Potchefstroom Campus), Private Bag X6001, Potchefstroom, South Africa

    Karin Terburgh, Jeremie Z. Lindeque, Francois H. van der Westhuizen & Roan Louw

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  1. Karin Terburgh
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  2. Jeremie Z. Lindeque
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  3. Francois H. van der Westhuizen
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  4. Roan Louw
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Contributions

KT and RL designed the research plan with input from JZL and FvdW. FvdW acquired the animal model and ethical approval with assistance from RL. RL and FvdW obtained funding for the study. KT performed the data processing with assistance from RL and JZL. KT analyzed the data and wrote the manuscript with input from RL, JZL and FvdW.

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Correspondence to Roan Louw.

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The authors declare no conflict of interest.

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The AnimCare animal research ethics committee of North-West University approved (NWU-0001-15-A5 and NWU-00378-16-A5) the animal protocols used in this study. All animals were maintained, and all procedures performed, in accordance with the code of ethics in research, training, and testing of drugs in South Africa and complied with national legislation.

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Terburgh, K., Lindeque, J.Z., van der Westhuizen, F.H. et al. Cross-comparison of systemic and tissue-specific metabolomes in a mouse model of Leigh syndrome. Metabolomics 17, 101 (2021). https://doi.org/10.1007/s11306-021-01854-8

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