Mitochondrial Metabolomics of Sym1-Depleted Yeast Cells Revealed Them to Be Lysine Auxotroph

Cells · 6 authors, 6 centres

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TL;DR

This preclinical study used compartment-specific metabolomics on yeast cells to investigate the function of the mitochondrial protein Sym1, the ortholog of human MPV17. The main finding was that Sym1-depleted yeast cells became lysine auxotrophs, unable to grow without lysine, and showed altered pyrimidine metabolism. A key limitation is that the study is conducted in yeast, so direct human clinical relevance is not established.

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BACKGROUND

The study aimed to elucidate the function of the mitochondrial inner membrane protein Sym1, the yeast ortholog of human MPV17, which is linked to mitochondrial DNA depletion syndrome (MDDS). The function of MPV17 remains undefined, and yeast models are used to study it. Methods: Researchers used Saccharomyces cerevisiae strains (sym1Δ and wildtype) and performed compartment-specific metabolomics on isolated mitochondria and cytoplasm. They combined gas chromatography–mass spectrometry (GC-MS) profiling with targeted liquid chromatography–mass spectrometry (LC-MS) and developed a U(H)PLC-QTOF/MS workflow focusing on significantly changed metabolites to reduce data complexity. Key Results: The analysis identified 51 significantly changed metabolites, with 41 being novel. The most significant finding was that sym1Δ cells were lysine auxotrophs, unable to grow without lysine at any tested temperature (19, 23, and 30 °C), while they could grow without arginine. Lysine biosynthesis intermediates (2-aminoadipate and saccharopine) were accumulated. Additionally, reduced carbamoyl-aspartate and orotic acid suggested a role for Sym1 in pyrimidine metabolism. Limitations: The study is preclinical, conducted in yeast, and does not directly test human cells or patients. The metabolic network is complex, and the exact mechanism by which Sym1 loss leads to lysine auxotrophy is not fully resolved. The isolation of mitochondria could potentially influence the metabolome. Implications: The findings suggest a potential link between lysine metabolism and human MDDS caused by MPV17 mutations, warranting future investigation. The compartment-specific metabolomics workflow is presented as a useful strategy for identifying altered metabolites in complex data.

STUDY TYPE

other

SPECIALTY

preclinical research

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ORIGINAL PAPER

PMC10000845

Mitochondrial Metabolomics of Sym1-Depleted Yeast Cells Revealed Them to Be Lysine Auxotroph

Cells

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ABSTRACT

Metabolomics has expanded from cellular to subcellular level to elucidate subcellular compartmentalization. By applying isolated mitochondria to metabolome analysis, the hallmark of mitochondrial metabolites has been unraveled, showing compartment-specific distribution and regulation of metabolites. This method was employed in this work to study a mitochondrial inner membrane protein Sym1, whose human ortholog MPV17 is related to mitochondria DNA depletion syndrome. Gas chromatography–mass spectrometry-based metabolic profiling was combined with targeted liquid chromatography–mass spectrometry analysis to cover more metabolites. Furthermore, we applied a workflow employing ultra-high performance liquid chromatography–quadrupole time of flight mass spectrometry with a powerful chemometrics platform, focusing on only significantly changed metabolites. This workflow highly reduced the complexity of acquired data without losing metabolites of interest. Consequently, forty-one novel metabolites were identified in addition to the combined method, of which two metabolites, 4-guanidinobutanal and 4-guanidinobutanoate, were identified for the first time in Saccharomyces cerevisiae . With compartment-specific metabolomics, we identified sym1 Δ cells as lysine auxotroph. The highly reduced carbamoyl-aspartate and orotic acid indicate a potential role of the mitochondrial inner membrane protein Sym1 in pyrimidine metabolism.

CITATION EXPORT

Simon Lagies, Daqiang Pan, Daniel A. Mohl et al.. Mitochondrial Metabolomics of Sym1-Depleted Yeast Cells Revealed Them to Be Lysine Auxotroph. Cells. (2023). https://doi.org/10.3390/cells12050692

AUTHORS

6 · 6 CENTRES

Simon Lagies, Daqiang Pan, Daniel A. Mohl, Dietmar A. Plattner, Ian E. Gentle, Bernd Kammerer

1Core Competence Metabolomics, Hilde-Mangold-Haus, University of Freiburg, 79104 Freiburg, Germany
2Institute of Organic Chemistry, University of Freiburg, 79104 Freiburg, Germany
3Institute of Pharmaceutical Science, University of Freiburg, 79104 Freiburg, Germany
4Institute of Medical Microbiology and Hygiene, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
5BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany
6Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg, Germany

EDITOR / REVIEWER

Carlo Vascotto, Ritva Tikkanen