| Co-Investigator(Kenkyū-buntansha) |
マルズキ サンコット モナッシュ大学, 生化学部, 助教授
リネン アンソニー・W. モナッシュ大学, 生化学部, 教授
TANAKA Masashi Faculty of Medicine, University of Nagoya, 医学部, 助手 (60155166)
MARZUKI Sangkot Monash University, Clayton, Victoria, Australia
LINNANE Anthony W. Monash University, Clayton, Victoria, Australia
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| Research Abstract |
The human mitochondrial genome (16,596 bp) encodes 13 mRNA genes for the oxidative phosphorylation system and 22 tRNA genes and two rRNA genes for mitochondrial protein synthesis. This project is concerned with the role of mitochondrial DNA (mtDNA) both in human degenerative diseases and in ageing processes. Our cooperative research between Japan and Australia, which are located in different hemisphere of the earth, has cancelled the environmental factors and the racial differences and has pick up the real molecular genetic changes responsible for degenerative diseases and ageing processes. The following achievements have been obtained during this project.
1. We have identified defects in the subunits of mitochondrial oxidative phosphorylation system as the molecular basis for mitochondrial encephalomyopathies (Tanaka, et al., BBRC 1988 ; Yoneda, et al., J. Neurol, Sci. 1989).
2. In order to further elucidate the genetic abnormality underlying the enzyme defects, we analyzed mtDNA from a
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mother and daughter both with chronic progressive external ophthalmoplegia (CPEO). Southern blot analysis revealed maternal inheritance of mutated mtDNA ; both patients had deleted mtDNA, though the deleted regions were different between them (Ozawa, et al., BBRC 1988).
3. Pleioplasmic multiple deletion in mtDNA was found in patients with familial CPEO (Sato, et al., BBRC 1989).
4. We detected multiple deletions of mtDNA in two brothers with exertional myoglobinuria (Ohno et al. Ann. Neurol., in press). This defect in the mitochondrial energy transducing system is a newly identified cause of recurrent myoglobinuria.
5. Association of cytoplasmic bodies and abnormal mitochondria was observed in the skeletal muscle of a patient with deleted mtDNA. This finding suggests that an abnormality in energy metabolism is involved in the pathogenesis of cytoplasmic bodies (Sahashi et al., J. Neurol, Sci. 1990).
7. Maternal inheritance of mtDNA point mutation was demonstrated in a Japanese family of Leber's hereditary optic neuropathy (Yoneda, et al., Lancet 1989).
8. Point mutations of mtDNA, including an A-to-G transition at position 3243 in the tRNA^<Leu> (UUR) gene in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, MELAS, (Tanaka et al., BBRC 1991 ; Ino et al., Lancet 1991), an A-to-G transition at position 8344 in the tRNA^<Lys> gene in myoclonus epilepsy associated with ragged-red fibers, MERRF, (Yoneda et al., Biochem Int 1991), and at position 4317 in the tRNA^<Ile> gene in fatal infantile mitochondrial cardiomyopathy, FICM, (Tanaka et al., Lancet 1990), were identified as the pathogenic genetic lesions.
9. We have proposed that the accumulation of mitochondrial genome mutation during the whole life of an individual is an important contributor to ageing and degenerative diseases (Linnane, et al., Lancet 1989).
10. Accumulation of deleted mtDNA has been demonstrated in the striatum of patients with Parkinson's disease (Tanaka et al., BBRC 1990 ; Ozawa et al., BBRC 1990), in the heart of patients with idiopathic cardiomyopathy (Hattoriet al., Am. Heart J. in press) and in the heart of aged individuals (Hattoriet al., Am. Heart J. in press). Less
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