INTRODUCTION OF DISEASE-RELATED MITOCHONDRIAL-DNA DELETIONS INTO HELA-CELLS LACKING MITOCHONDRIAL-DNA RESULTS IN MITOCHONDRIAL DYSFUNCTION

被引:501
作者
HAYASHI, JI
OHTA, S
KIKUCHI, A
TAKEMITSU, M
GOTO, Y
NONAKA, I
机构
[1] JICHI MED SCH,DEPT BIOCHEM,MINAMI KAWACHI,TOCHIGI 32904,JAPAN
[2] NATL CTR NEUROL & PSYCHIAT,NATL INST NEUROSCI,DIV ULTRASTRUCT RES,KODAIRA,TOKYO 187,JAPAN
关键词
MITOCHONDRIAL ENCEPHALOMYOPATHY; MTDNA DELETION; INTERCELLULAR MTDNA TRANSFER; MITOCHONDRIAL DYSFUNCTION;
D O I
10.1073/pnas.88.23.10614
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Mutant mitochondrial DNA with large-scale deletions (DELTA-mtDNA) has been frequently observed in patients with chronic progressive external ophthalmoplegia (CPEO), a subgroup of the mitochondrial encephalomyopathies. To exclude involvement of the nuclear genome in expression of the mitochondrial dysfunction characteristic of CPEO, we introduced the mtDNA of a CPEO patient into clonal mtDNA-less HeLa cells and isolated cybrid clones. Quantitation of DELTA-MtDNA in the cybrids revealed that DELTA-mtDNA was selectively propagated with higher levels of DELTA-mtDNA correlating with slower cellular growth rate. In these cybrid clones, translational complementation of the missing tRNAs occurred only when DELTA-mtDNA was < 60% of the total mtDNA, whereas accumulation of DELTA-mtDNA to > 60% resulted in progressive inhibition of overall mitochondrial translation as well as reduction of cytochrome c oxidase activity throughout the organelle population. Because these cybrids shared the same nuclear background as HeLa cells, these results suggest that large-scale deletion mutations of mtDNA alone are sufficient for the mitochondrial dysfunction characteristic of CPEO.
引用
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页码:10614 / 10618
页数:5
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