Bioenergetic consequences of accumulating the common 4977-bp mitochondrial DNA deletion

被引:132
作者
Porteous, WK
James, AM
Sheard, PW
Porteous, CM
Packer, MA
Hyslop, SJ
Melton, JV
Pang, CY
Wei, YH
Murphy, MP
机构
[1] Univ Otago, Dept Biochem, Dunedin, New Zealand
[2] Univ Otago, Dept Physiol, Dunedin, New Zealand
[3] Natl Yang Ming Univ, Ctr Cellular & Mol Biol, Taipei 112, Taiwan
[4] Natl Yang Ming Univ, Dept Biochem, Taipei 112, Taiwan
来源
EUROPEAN JOURNAL OF BIOCHEMISTRY | 1998年 / 257卷 / 01期
关键词
mitochondrial DNA; bioenergetic defect; chronic progressive external ophthalmoplegia; cybrids;
D O I
10.1046/j.1432-1327.1998.2570192.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mutations and deletions ill mitochondrial DNA (mtDNA) lead to a number of human diseases characterized by neuromuscular degeneration, Accumulation of truncated mtDNA molecules (Delta-mtDNA) lacking a specific 4977-bp fragment, the common deletion, leads to three related mtDNA diseases: Pearson's syndrome: Kearns-Sayre syndrome; and chronic progressive external ophthalmoplegia (CPEO). In addition. the proportion of Delta-mtDNA present increases with age in a range of tissues. Consequently, there is considerable interest in the effects of the accumulation of Delta-mtDNA on cell function. The 4977-bp deletion affects genes encoding 7 polypeptide components of the mitochondrial respiratory chain, and 5 of the 22 tRNAs necessary for mitochondrial protein synthesis. To determine how the :accumulation of Delta-mtDNA affects oxidative phosphorylation we constructed a series of cybrids by fusing a human osteosarcoma cell line depleted of mtDNA (rho degrees) with enucleated skin fibroblasts from a CPEO patient. The ensuing cybrids contained 0-86% Delta-mtDNA and all had volumes, protein contents, plasma-membrane potentials and mitochondrial contents similar to those of the parental cell line. The bioenergetic consequences of accumulating Delta-mtDNA were assessed by measuring the mitochondrial membrane potential, rate of ATP synthesis and ATP/ADP ratio. In cybrids containing less than 50-55% Delta-mtDNA, these bioenergetic functions were equivalent to those of cybrids with intact mtDNA. However, once the proportion of Delta-mtDNA exceeded this threshold, the mitochondrial membrane potential, rate of ATP synthesis. and cellular ATP/ADP ratio decreased. These bioenergetic deficits will contribute to the cellular pathology associated with the accumulation of Delta-mtDNA in the target tissues of patients with mtDNA diseases.
引用
收藏
页码:192 / 201
页数:10
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