The study of cauces of mitochondrial cytopathy

• Project/Area Number: 05670679
• Research Category: Grant-in-Aid for General Scientific Research (C)
• Allocation Type: Single-year Grants
• Research Field: Pediatrics
• Research Institution: University of Tokushima
• Principal Investigator: ITO Michinori Department of Pediatrics, School of Medicine, University of Tokushima Instructor, 医学部, 講師 (40211057)
• Co-Investigator(Kenkyū-buntansha): KURODA Yasuhiro Department of Pediatrics, School of Medicine, University of Tokushima Professor, 医学部, 教授 (20035471)
• Project Period (FY): 1993 – 1994
• Project Status: Completed (Fiscal Year 1994)
• Budget Amount: ¥2,100,000 (Direct Cost: ¥2,100,000); Fiscal Year 1994: ¥500,000 (Direct Cost: ¥500,000); Fiscal Year 1993: ¥1,600,000 (Direct Cost: ¥1,600,000)
• Keywords: Mitochondrial cytopathy / import of mitichonrial protein / pyruvate dehydrogenase / mitochondria / pyruvate dehydrogenase deficiency

Research Abstract

Most of mitochondrial enzyme proteins are synthesized in the cytoplasm as precursor enzyme proteins and are subsequently imported into mitochondria to form mature enzyme proteins. The defect in this import system might be cause the mitochondrial cytopathy with sever clinical symptoms due to disturbance of mitochondrial functions. Recently we found the patient with defect of multiple mitochondrial enzymes containing pyruvate dehydrogenase (PDH) complex. In this project, to determine the primary defect in this patient we examined the import system of precursor proteins of PDH (pEla and pElb) into mitochondria in fibroblasts from the patient using cell-labeling and pulse-chase methods. The rates of import of pEla and pElb into mitochondria in fibroblasts from the patient decreased to about 40% and 63% of those in normal control fibroblasts, respectively. These results showed the defect of import system of Ela na Elb into mitochondria in this patient. Since the patient had not only the defect of PDH complex but also the defect of other mitochondrial enzymes and cDNAs for pEla and pElb in the patient had no mutation, the primary defect in this patient is in the import system of mitochondrila enzyme proteins into mitochondria.
In anotheer study, we found a new 18bp insertion mutation in the gene for a subunit of PDH in afemale patient with PDH deficiency, the common cause of mitochondrial cytopathy, and the wide variation in the expression of mutant gene in cultcred cells from this patent. These results showed that female patients with PDH deficiency might be misdiagnosed only with enzymological diagnosis. Therefore, it is necessry to develop the new diagnosis method of PDH deficiency, such as DNA analysis.

Research Products

• [Publications] Michinori Ito et al: "Molecular genetic analysis of a female patient with pyruvate dehydrogenase deficiency:Detection of a new mutation and differentail expression of mutant gene in cultured cells" J Inher Metabol Dis. (in press).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] "Molecular genetic analysis of a female patient with pyruvate dehydrogenase deficiency : detection of a new mutation and deferential expression of mutant gene product in cultured cells." (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Michinori Ito et al: "Molecular gsultic anrlysis of a beuale patient with pyruvate dehydugasd deficiency:Dstertinb a new wtitis and dlggenantirl expressing mutent gene prochuitin in cultusid cells" J.Inher.Metal.Dis.(in press.).