A pathogenic 15-base pair deletion in mitochondrial DNA-encoded cytochrome c oxidase subunit III results in the absence of functional cytochrome c oxidase

被引:45
作者
Hoffbuhr, KC
Davidson, E
Filiano, BA
Davidson, M
Kennaway, NG
King, MP
机构
[1] Thomas Jefferson Univ, Dept Mol Pharmacol & Biochem, Philadelphia, PA 19107 USA
[2] Oregon Hlth Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA
[3] Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA
关键词
D O I
10.1074/jbc.275.18.13994
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
A 15-base pair, in-frame, deletion (9480del15) in the mitochondrial DNA (mtDNA)-encoded cytochrome c oxidase subunit III (COX III) gene was identified previously in a patient with recurrent episodes of myoglobinuria and an isolated COX deficiency. Transmitochondrial cell lines harboring 0, 97, and 100% of the 9480del15 deletion were created by fusing human cells lacking mtDNA (rho(o) cells) with platelet and lymphocyte fractions isolated from the patient. The COX III gene mutation resulted in a severe respiratory chain defect in all mutant cell lines. Cells homoplasmic for the mutation had no detectable COX activity or respiratory ATP synthesis, and required uridine and pyruvate supplementation for growth, a phenotype similar to rho(o) cells. The cells with 97% mutated mtDNA exhibited severe reductions in both COX activity (6% of wild-type levels) and rates of ATP synthesis (9% of wild-type). The COX III polypeptide in the mutant cells, although translated at rates similar to wild-type, had reduced stability. There was no evidence for assembly of COX I, COX II, or COX III subunits in a multisubunit complex in cells homoplasmic for the mutation, thus indicating that there was no stable assembly of COX I with COX II in the absence of wild-type COX III. In contrast, the COX I and COX II subunits were assembled in cells with 97% mutated mtDNA.
引用
收藏
页码:13994 / 14003
页数:10
相关论文
共 55 条
[1]   Intracellular mitochondrial triplasmy in a patient with two heteroplasmic base changes [J].
Bidooki, SK ;
Johnson, MA ;
ChrzanowskaLightowlers, Z ;
Bindoff, LA ;
Lightowlers, RN .
AMERICAN JOURNAL OF HUMAN GENETICS, 1997, 60 (06) :1430-1438
[2]   FATAL LACTIC-ACIDOSIS IN INFANCY WITH A DEFECT OF COMPLEX-III OF THE RESPIRATORY-CHAIN [J].
BIRCHMACHIN, MA ;
SHEPHERD, IM ;
WATMOUGH, NJ ;
SHERRATT, HSA ;
BARTLETT, K ;
DARLEYUSMAR, VM ;
MILLIGAN, DWA ;
WELCH, RJ ;
AYNSLEYGREEN, A ;
TURNBULL, DM .
PEDIATRIC RESEARCH, 1989, 25 (05) :553-559
[3]   CYTOCHROME-C-OXIDASE - SUBUNIT STRUCTURE AND PROTON PUMPING [J].
BRUNORI, M ;
ANTONINI, G ;
MALATESTA, F ;
SARTI, P ;
WILSON, MT .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1987, 169 (01) :1-8
[4]   STRUCTURE AND FUNCTION OF CYTOCHROME-C-OXIDASE [J].
CAPALDI, RA .
ANNUAL REVIEW OF BIOCHEMISTRY, 1990, 59 :569-596
[5]  
Chomyn A, 1996, Methods Enzymol, V264, P197, DOI 10.1016/S0076-6879(96)64020-8
[6]  
Chomyn A, 1996, Methods Enzymol, V264, P334, DOI 10.1016/S0076-6879(96)64031-2
[7]   INVITRO GENETIC TRANSFER OF PROTEIN-SYNTHESIS AND RESPIRATION DEFECTS TO MITOCHONDRIAL DNA-LESS CELLS WITH MYOPATHY-PATIENT MITOCHONDRIA [J].
CHOMYN, A ;
MEOLA, G ;
BRESOLIN, N ;
LAI, ST ;
SCARLATO, G ;
ATTARDI, G .
MOLECULAR AND CELLULAR BIOLOGY, 1991, 11 (04) :2236-2244
[8]   MELAS MUTATION IN MTDNA BINDING-SITE FOR TRANSCRIPTION TERMINATION FACTOR CAUSES DEFECTS IN PROTEIN-SYNTHESIS AND IN RESPIRATION BUT NO CHANGE IN LEVELS OF UPSTREAM AND DOWNSTREAM MATURE TRANSCRIPTS [J].
CHOMYN, A ;
MARTINUZZI, A ;
YONEDA, M ;
DAGA, A ;
HURKO, O ;
JOHNS, D ;
LAI, ST ;
NONAKA, I ;
ANGELINI, C ;
ATTARDI, G .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (10) :4221-4225
[9]  
COSTANTINO P, 1977, J BIOL CHEM, V252, P1702
[10]  
Davey GP, 1996, J NEUROCHEM, V66, P1617