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A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells.

ABSTRACT: Mutations in either the mitochondrial or nuclear genomes can give rise to respiratory chain disease (RCD), a large class of devastating metabolic disorders. Their clinical management is challenging, in part because we lack facile and accurate biomarkers to aid in diagnosis and in the monitoring of disease progression. Here we introduce a sequential strategy that combines biochemical analysis of spent media from cell culture with analysis of patient plasma to identify disease biomarkers. First, we applied global metabolic profiling to spotlight 32 metabolites whose uptake or secretion kinetics were altered by chemical inhibition of the respiratory chain in cultured muscle . These metabolites span a wide range of pathways and include lactate and alanine, which are used clinically as biomarkers of RCD. We next measured the cell culture-defined metabolites in human plasma to discover that creatine is reproducibly elevated in two independent cohorts of RCD patients, exceeding lactate and alanine in magnitude of elevation and statistical significance. In cell culture extracellular creatine was inversely related to the intracellular phosphocreatine:creatine ratio suggesting that the elevation of plasma creatine in RCD patients signals a low energetic state of tissues using the phosphocreatine shuttle. Our study identifies plasma creatine as a potential biomarker of human mitochondrial dysfunction that could be clinically useful. More generally, we illustrate how spent media from cellular models of disease may provide a window into the biochemical derangements in human plasma, an approach that could, in principle, be extended to a range of complex diseases.

SUBMITTER: Shaham O

PROVIDER: S-EPMC2824369 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells.

Shaham Oded O Slate Nancy G NG Goldberger Olga O Xu Qiuwei Q Ramanathan Arvind A Souza Amanda L AL Clish Clary B CB Sims Katherine B KB Mootha Vamsi K VK

Proceedings of the National Academy of Sciences of the United States of America 20100108 4

Mutations in either the mitochondrial or nuclear genomes can give rise to respiratory chain disease (RCD), a large class of devastating metabolic disorders. Their clinical management is challenging, in part because we lack facile and accurate biomarkers to aid in diagnosis and in the monitoring of disease progression. Here we introduce a sequential strategy that combines biochemical analysis of spent media from cell culture with analysis of patient plasma to identify disease biomarkers. First, w ...[more]

PMID: 20080599

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Project description:BackgroundIdentification of a non-invasive technique to assess embryo implantation potential in assisted reproduction would greatly increase success rates and lead more efficiently to single embryo transfer. Early studies suggested metabonomic analysis of spent culture media could improve embryo selection. The goal of this study is to assess if embryo implantation can be predicted based on proton nuclear magnetic resonance ((1)H NMR) profiles of spent embryo culture media from patients undergoing transfer of multiple embryos on cycle day 3.MethodWe conducted a retrospective study in an academic assisted reproduction technology (ART) program and analyzed the data in a university research center. Two hundred twenty-eight spent culture media samples originating from 108 patients were individually analyzed. Specifically, five distinct sets (1 to 5) of different types of spent media samples (volume ~14 μL) from embryos that resulted in clinical pregnancy (positive heart rate at 6 weeks gestation) (n (1) = 29; n (2) = 19; n (3) = 9; n (4) = 12; n (5) = 33; n (total) = 102) and from embryos that did not implant (n (1) = 28; n (2) = 29; n (3) = 18; n (4) = 15; n (5) = 36; n (total) = 126) were collected on day 3 of embryo growth. The media samples were profiled using (1)H NMR spectroscopy, and the NMR profiles of sets 1 to 5 were subject to standard uni- and multi-variate data analyses in order to evaluate potential correlation of profiles with implantation success.ResultsFor set 1 of the media samples, a borderline class separation of NMR profiles was obtained by use of principal component analysis (PCA) and logistic regression. This tentative class separation could not be repeated and validated in any of the other media sets 2 to 5.ConclusionsDespite the rigorous technical approach, (1)H NMR based profiling of spent culture media cannot predict success of implantation for day 3 human embryos.

Dataset Information

A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells.

Publications

A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells.

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