Scientific Publications

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

Publication TypeJournal Article
AuthorsShaham, O., Xu Q., Ramanathan A., Souza AL, Clish CB, and Mootha VK
AbstractMutations 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.
Year of Publication2010
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue4
Pages1571-5
Date Published (YYYY/MM/DD)2010/01/26
ISSN Number0027-8424
DOI10.1073/pnas.0906039107
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/20080599?dopt=Abstract