Primary mitochondrial respiratory chain (MRC) disease causes an extensive array of multi-system findings characterized by impaired energy metabolism that affects 1 in 5,000 individuals across a lifetime. Unfortunately, diagnosis of this class of disorders is complicated by the absence of a biomarker that divulges all cases with sufficient sensitivity or specificity. Thus, despite arduous diagnostic efforts, objective evidence of mitochondrial dysfunction is commonly not obtained for clinically suspected mitochondrial disease patients. Significant bioinformatic advances have made it feasible to consider addressing this diagnostic challenge from a novel, systems-biology perspective. The proposed approach is based on the hypothesis that MRC dysfunction in humans is accompanied by cellular adaptations identifiable at the level of biochemical pathway expression alterations.
The specific aim of this proposal is to determine if transcriptional alterations across biochemical pathways occur in patients with confirmed MRC disease. Recognition of specific adaptive changes in gene expression patterns among biologically-relevant pathways in human tissues will permit the pursuit of two overall goals. First, is to elucidate biochemical mechanisms by which primary MRC dysfunction results in clinical disease. This will provide insight into secondary metabolic consequences of genetically-based mitochondrial disease which may be amenable to therapeutic intervention. Second, is to identify a """"""""signature"""""""" of primary MRC dysfunction in humans based on these biochemical pathway expression alterations. This will permit the development of a systems biology-based """"""""biomarker"""""""" with the potential to guide the molecular diagnosis of human MRC disease. The long-term objective is to develop a minimally-invasive screening assay used to estimate the likelihood of primary MRC disease in suspected patients regardless of individual pathogenic cause. This grant proposes to apply biochemical pathway cluster analysis to global genome transcriptional profiling in tissues from clinically symptomatic patients with confirmed MRC disease. Global genome expression patterns will be studied by Affymetrix microarray analysis using RNA isolated both from skeletal muscle tissue (subaim A) and from minimally-invasively obtained specimens (cultured fibroblast cell lines and blood lymphoblastoid cell lines) (subaim B) in patients with biopsy-proven MRC dysfunction and, when possible, confirmed pathogenic mutations. Multiple tissues will be studied from a given MRC disease patient in an effort to determine if identified expression alterations are unique to clinically affected tissue or common to minimally-invasively obtained, asymptomatic tissues as well. Age-, gender-, and race-matched control specimens will be carefully selected for each tissue type. Data analysis will primarily utilize gene set enrichment analysis of biochemical pathway clusters curated from in silico databases.

Public Health Relevance

Primary mitochondrial respiratory chain disease is comprised of hundreds of individual genetic disorders which cause a wide variety of energy-related problems that may involve almost every system in the body. Mitochondrial disease diagnosis is complicated by the absence of a single biomarker that satisfactorily divulges all cases. Identifying a signature of mitochondrial disease based upon the genetic alterations that mitochondrial dysfunction causes in cells will offer the opportunity for improved diagnosis, treatment, and ideally, cure.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Hyde, James F
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Children's Hospital of Philadelphia
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Zhang, Zhe; Falk, Marni J (2014) Integrated transcriptome analysis across mitochondrial disease etiologies and tissues improves understanding of common cellular adaptations to respiratory chain dysfunction. Int J Biochem Cell Biol 50:106-11
Falk, Marni J; Li, Dong; Gai, Xiaowu et al. (2014) AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelination, and Reduced N-Acetylaspartate. JIMD Rep 14:77-85
Zhang, Zhe; Tsukikawa, Mai; Peng, Min et al. (2013) Primary respiratory chain disease causes tissue-specific dysregulation of the global transcriptome and nutrient-sensing signaling network. PLoS One 8:e69282
Gai, Xiaowu; Ghezzi, Daniele; Johnson, Mark A et al. (2013) Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy. Am J Hum Genet 93:482-95
Clarke, Colleen; Xiao, Rui; Place, Emily et al. (2013) Mitochondrial respiratory chain disease discrimination by retrospective cohort analysis of blood metabolites. Mol Genet Metab 110:145-52
McCormick, Elizabeth; Place, Emily; Falk, Marni J (2013) Molecular genetic testing for mitochondrial disease: from one generation to the next. Neurotherapeutics 10:251-61
Schrier, Samantha A; Wong, Lee-Jun; Place, Emily et al. (2012) Mitochondrial tRNA-serine (AGY) m.C12264T mutation causes severe multisystem disease with cataracts. Discov Med 13:143-50
Dingley, Stephen; Chapman, Kimberly A; Falk, Marni J (2012) Fluorescence-activated cell sorting analysis of mitochondrial content, membrane potential, and matrix oxidant burden in human lymphoblastoid cell lines. Methods Mol Biol 837:231-9
Falk, Marni J; Pierce, Eric A; Consugar, Mark et al. (2012) Mitochondrial disease genetic diagnostics: optimized whole-exome analysis for all MitoCarta nuclear genes and the mitochondrial genome. Discov Med 14:389-99
Falk, Marni J; Zhang, Qi; Nakamaru-Ogiso, Eiko et al. (2012) NMNAT1 mutations cause Leber congenital amaurosis. Nat Genet 44:1040-5

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