A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies.

Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity. Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production and mitochondrial disorders. More than 250 genes that cause mitochondrial disorders have been reported to date. However exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed comprehensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration analyses using high-density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and 3 mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as novel causative genes. We also identified 2 genes known to cause monogenic diseases (MECP2 and TNNI3) and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21) as causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic heterogeneity and will improve patient care of this complex disorder.

Establishment of a post-race biomarkers database and application of pathway analysis to identify potential biomarkers in post-race equine plasma.

In the context of doping control, conventional direct chemical testing detects only a limited scope of target substances in equine biological samples. To expand the ability to detect doping agents and their detection windows, metabolomics has recently become a common approach for monitoring alteration of biomarkers caused by doping agents in relevant metabolic pathways. In horse racing, remarkable changes in metabolic profiles between the rest state and racing are likely to affect the identification of doping biomarkers. Previously, we reported a limited number of significantly upregulated metabolites after racing, based on a non-targeted metabolomics approach using out-of-competition and post-race equine plasma samples. In this study, we performed a more thorough analysis of the data set, using pathway analysis to establish a post-race biomarkers database (PBD) that includes upregulated and downregulated metabolites, their fold changes, and relevant pathways, with the main objective of improving our understanding of changes in physiological status related to horse racing. Statistical analysis of the PBD revealed that two peak combinations of pentadecanoyl carnitine/galactosylglycerol (P/G) and heptadecanoyl carnitine/galactosylglycerol (H/G) could be used as potential biomarkers for the discrimination of the rest and post-race groups. To demonstrate the applicability of the PBD, we validated the post-race biomarkers P/G and H/G (highly involved in lipid metabolism) by a single-blind test. This strategy, which combines establishment of a biomarker database with pathway analysis, represents a powerful tool for discovering potential doping biomarkers in the future.

Ski3/TTC37 deficiency associated with trichohepatoenteric syndrome causes mitochondrial dysfunction in Drosophila.

Tetratricopeptide repeat protein 37 (TTC37) is a causative gene of trichohepatoenteric syndrome (THES). However, little is known about the pathogenesis of this disease. Here, we characterize the phenotype of a Drosophila model in which ski3, a homolog of TTC37, is disrupted. The mutant flies are pupal lethal, and the pupal lethality is partially rescued by transgenic expression of wild-type ski3 or human TTC37. The mutant larvae show growth retardation, heart arrhythmia, triacylglycerol accumulation, and aberrant metabolism of glycolysis and the TCA cycle. Moreover, mitochondrial membrane potential and respiratory chain complex activities are significantly reduced in the mutants. Our results demonstrate that ski3 deficiency causes mitochondrial dysfunction, which may underlie the pathogenesis of THES.