Analysis of Leigh Syndrome Mutations in the Yeast SURF1 Homolog Reveals a New Member of the Cytochrome Oxidase Assembly Factor Family

被引:32
作者
Bestwick, Megan
Jeong, Mi-Young
Khalimonchuk, Oleh
Kim, Hyung
Winge, Dennis R. [1 ]
机构
[1] Univ Utah, Hlth Sci Ctr, Dept Med, Salt Lake City, UT 84132 USA
基金
美国国家卫生研究院;
关键词
C-OXIDASE; SACCHAROMYCES-CEREVISIAE; MITOCHONDRIAL COX1P; DEFICIENCY; SCO1; EXPRESSION; DEFECTS; BINDING; HEME; BIOGENESIS;
D O I
10.1128/MCB.00228-10
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
Three missense SURF1 mutations identified in patients with Leigh syndrome (LS) were evaluated in the yeast homolog Shy1 protein. Introduction of two of the Leigh mutations, (FT)-T-249 and (YD)-D-344, in Shy1 failed to significantly attenuate the function of Shy1 in cytochrome c oxidase (CcO) biogenesis as seen with the human mutations. In contrast, a G(137)E substitution in Shy1 results in a nonfunctional protein conferring a CcO deficiency. The G(137)E Shy1 mutant phenocopied shy1 Delta cells in impaired Cox1 hemylation and low mitochondrial copper. A genetic screen for allele-specific suppressors of the G(137)E Shy1 mutant revealed Coa2, Cox10, and a novel factor designated Coa4. Coa2 and Cox10 are previously characterized CcO assembly factors. Coa4 is a twin CX9C motif mitochondrial protein localized in the intermembrane space and associated with the inner membrane. Cells lacking Coa4 are depressed in CcO activity but show no impairment in Cox1 maturation or formation of the Shy1-stabilized Cox1 assembly intermediate. To glean insights into the functional role of Coa4 in CcO biogenesis, an unbiased suppressor screen of coa4 Delta cells was conducted. Respiratory function of coa4 Delta cells was restored by the overexpression of CYC1 encoding cytochrome c. Cyc1 is known to be important at an ill-defined step in the assembly and/or stability of CcO. This new link to Coa4 may begin to further elucidate the role of Cyc1 in CcO biogenesis.
引用
收藏
页码:4480 / 4491
页数:12
相关论文
共 47 条
[1]   Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency [J].
Antonicka, H ;
Leary, SC ;
Agar, JN ;
Horvath, R ;
Kennaway, NG ;
Harding, CO ;
Jaksch, M ;
Shoubridge, EA .
HUMAN MOLECULAR GENETICS, 2003, 12 (20) :2693-2702
[2]   Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy [J].
Antonicka, H ;
Mattman, A ;
Carlson, CG ;
Glerum, DM ;
Hoffbuhr, KC ;
Leary, SC ;
Kennaway, NG ;
Shoubridge, EA .
AMERICAN JOURNAL OF HUMAN GENETICS, 2003, 72 (01) :101-114
[3]   Mss51p and Cox14p jointly regulate mitochondrial Cox1p expression in Saccharomyces cerevisiae [J].
Barrientos, A ;
Zambrano, A ;
Tzagoloff, A .
EMBO JOURNAL, 2004, 23 (17) :3472-3482
[4]   Cytochrome oxidase assembly does not require catalytically active cytochrome c [J].
Barrientos, A ;
Pierre, D ;
Lee, J ;
Tzagoloff, A .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (11) :8881-8887
[5]   Shy1p is necessary for full expression of mitochondrial COX1 in the yeast model of Leigh's syndrome [J].
Barrientos, A ;
Korr, D ;
Tzagoloff, A .
EMBO JOURNAL, 2002, 21 (1-2) :43-52
[6]   Suppression mechanisms of COX assembly defects in yeast and human: Insights into the COX assembly process [J].
Barrientos, Antoni ;
Gouget, Karine ;
Horn, Darryl ;
Soto, Ileana C. ;
Fontanesi, Flavia .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2009, 1793 (01) :97-107
[7]   The Role of Coa2 in Hemylation of Yeast Cox1 Revealed by Its Genetic Interaction with Cox10 [J].
Bestwick, Megan ;
Khalimonchuk, Oleh ;
Pierrel, Fabien ;
Winge, Dennis R. .
MOLECULAR AND CELLULAR BIOLOGY, 2010, 30 (01) :172-185
[8]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[9]   Complementation analysis of systemic cytochrome oxidase deficiency presenting as Leigh syndrome [J].
Brown, RM ;
Brown, GK .
JOURNAL OF INHERITED METABOLIC DISEASE, 1996, 19 (06) :752-760
[10]   Surf1, Associated with Leigh Syndrome in Humans, Is a Heme-binding Protein in Bacterial Oxidase Biogenesis [J].
Bundschuh, Freya A. ;
Hannappel, Achim ;
Anderka, Oliver ;
Ludwig, Bernd .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (38) :25735-25741