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

被引:121
作者
Shaham, Oded [1 ,3 ,4 ]
Slate, Nancy G. [1 ]
Goldberger, Olga [1 ]
Xu, Qiuwei [6 ]
Ramanathan, Arvind [3 ]
Souza, Amanda L. [3 ]
Clish, Clary B. [3 ]
Sims, Katherine B. [1 ,2 ,5 ]
Mootha, Vamsi K. [1 ,3 ,4 ]
机构
[1] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA
[2] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA
[3] MIT & Harvard, Broad Inst, Cambridge, MA 02142 USA
[4] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA
[5] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA
[6] Merck Res Labs, West Point, PA 19486 USA
基金
美国国家卫生研究院;
关键词
biochemical genetics; biomarker; metabolomics; mitochondria; MAGNETIC-RESONANCE SPECTROSCOPY; DISORDERS; CREATINE; CHILDREN; CLASSIFICATION; BIOSYNTHESIS; PREVALENCE; CRITERIA; MUTANTS;
D O I
10.1073/pnas.0906039107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:1571 / 1575
页数:5
相关论文
共 29 条
[1]   High-throughput classification of yeast mutants for functional genomics using metabolic footprinting [J].
Allen, J ;
Davey, HM ;
Broadhurst, D ;
Heald, JK ;
Rowland, JJ ;
Oliver, SG ;
Kell, DB .
NATURE BIOTECHNOLOGY, 2003, 21 (06) :692-696
[2]   Functional evaluation techniques in mitochondrial disorders [J].
Argov, Z .
EUROPEAN NEUROLOGY, 1998, 39 (02) :65-71
[3]   INVESTIGATION OF HUMAN MITOCHONDRIAL MYOPATHIES BY PHOSPHORUS MAGNETIC-RESONANCE SPECTROSCOPY [J].
ARNOLD, DL ;
TAYLOR, DJ ;
RADDA, GK .
ANNALS OF NEUROLOGY, 1985, 18 (02) :189-196
[4]   Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia [J].
Atkuri, Kondala R. ;
Cowan, Tina M. ;
Kwan, Tony ;
Ng, Angelina ;
Herzenberg, Leonard A. ;
Herzenberg, Leonore A. ;
Enns, Gregory M. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (10) :3941-3945
[5]   Metabolomic approaches to mitochondrial disease: correlation of urine organic acids [J].
Barshop, BA .
MITOCHONDRION, 2004, 4 (5-6) :521-527
[6]   Diagnostic criteria for respiratory chain disorders in adults and children [J].
Bernier, FP ;
Boneh, A ;
Dennett, X ;
Chow, CW ;
Cleary, MA ;
Thorburn, DR .
NEUROLOGY, 2002, 59 (09) :1406-1411
[7]   Mechanisms of disease: Mitochondrial respiratory-chain diseases [J].
DiMauro, S ;
Schon, EA .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 348 (26) :2656-2668
[8]   Creatine accumulation and exchange by HEK293 cells stably expressing high levels of a creatine transporter [J].
Dodd, JR ;
Zheng, T ;
Christie, DL .
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 1999, 1472 (1-2) :128-136
[9]   PHOSPHORUS MAGNETIC-RESONANCE SPECTROSCOPY OF PATIENTS WITH MITOCHONDRIAL CYTOPATHIES DEMONSTRATES DECREASED LEVELS OF BRAIN PHOSPHOCREATINE [J].
ELEFF, SM ;
BARKER, PB ;
BLACKBAND, SJ ;
CHATHAM, JC ;
LUTZ, NW ;
JOHNS, DR ;
BRYAN, RN ;
HURKO, O .
ANNALS OF NEUROLOGY, 1990, 27 (06) :626-630
[10]   Metabolic pathway profiling of mitochondrial respiratory chain mutants in C. elegans [J].
Falk, M. J. ;
Zhang, Z. ;
Rosenjack, J. R. ;
Nissim, I. ;
Daikhin, E. ;
Nissim, I. ;
Sedensky, M. M. ;
Yudkoff, M. ;
Morgan, P. G. .
MOLECULAR GENETICS AND METABOLISM, 2008, 93 (04) :388-397