Respiratory chain supercomplexes set the threshold for respiration defects in human mtDNA mutant cybrids

被引:102
作者
D'Aurelio, Marilena
Gajewski, Carl D.
Lenaz, Giorgio
Manfredi, Giovanni
机构
[1] Cornell Univ, Dept Neurol & Neurosci, Weill Med Coll, New York, NY 10021 USA
[2] Univ Bologna, Dipartimento Biochim G Moruzzi, I-40126 Bologna, Italy
关键词
D O I
10.1093/hmg/ddl141
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
Mitochondrial DNA (mtDNA) mutations cause heterogeneous disorders in humans. MtDNA exists in multiple copies per cell, and mutations need to accumulate beyond a critical threshold to cause disease, because coexisting wild-type mtDNA can complement the genetic defect. A better understanding of the molecular determinants of functional complementation among mtDNA molecules could help us shedding some light on the mechanisms modulating the phenotypic expression of mtDNA mutations in mitochondrial diseases. We studied mtDNA complementation in human cells by fusing two cell lines, one containing a homoplasmic mutation in a subunit of respiratory chain complex IV, COX I, and the other a distinct homoplasmic mutation in a subunit of complex III, cytochrome b. Upon cell fusion, respiration is recovered in hybrids cells, indicating that mitochondria fuse and exchange genetic and protein materials. Mitochondrial functional complementation occurs frequently, but with variable efficiency. We have investigated by native gel electrophoresis the molecular organization of the mitochondrial respiratory chain in complementing hybrid cells. We show that the recovery of mitochondrial respiration correlates with the presence of supramolecular structures (supercomplexes) containing complexes I, III and IV. We suggest that critical amounts of complexes III or IV are required in order for supercomplexes to form and provide mitochondrial functional complementation. From these findings, supercomplex assembly emerges as a necessary step for respiration, and its defect sets the threshold for respiratory impairment in mtDNA mutant cells.
引用
收藏
页码:2157 / 2169
页数:13
相关论文
共 39 条
[1]   Respiratory complex III is required to maintain complex I in mammalian mitochondria [J].
Acín-Pérez, R ;
Bayona-Bafaluy, MP ;
Fernández-Silva, P ;
Moreno-Loshuertos, R ;
Perez-Martos, A ;
Bruno, C ;
Moraes, CT ;
Enríquez, JA .
MOLECULAR CELL, 2004, 13 (06) :805-815
[2]  
ATTARDI G, 1988, ANNU REV CELL BIOL, V4, P289, DOI 10.1146/annurev.cb.04.110188.001445
[3]   The mitochondrial respiratory chain is partially organized in a supercomplex assembly - Kinetic evidence using flux control analysis [J].
Bianchi, C ;
Genova, ML ;
Castelli, GP ;
Lenaz, G .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (35) :36562-36569
[4]   A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast [J].
Blakely, EL ;
Mitchell, AL ;
Fisher, N ;
Meunier, B ;
Nijtmans, LG ;
Schaefer, AM ;
Jackson, MJ ;
Turnbull, DM ;
Taylor, RW .
FEBS JOURNAL, 2005, 272 (14) :3583-3592
[5]  
Brookes PS, 2002, PROTEOMICS, V2, P969, DOI 10.1002/1615-9861(200208)2:8<969::AID-PROT969>3.0.CO
[6]  
2-3
[7]   Functional F1-ATPase essential in maintaining growth and membrane potential of human mitochondrial DNA-depleted ρ° cells [J].
Buchet, K ;
Godinot, C .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (36) :22983-22989
[8]   METHOD FOR THE LOCALIZATION OF SITES FOR OXIDATIVE PHOSPHORYLATION [J].
CHANCE, B ;
WILLIAMS, GR .
NATURE, 1955, 176 (4475) :250-254
[9]   Emerging functions of mammalian mitochondrial fusion and fission [J].
Chen, HC ;
Chan, DC .
HUMAN MOLECULAR GENETICS, 2005, 14 :R283-R289
[10]   In vivo regulation of oxidative phosphorylation in cells harboring a stop-codon mutation in mitochondrial DNA-encoded cytochrome c oxidase subunit I [J].
D'Aurelio, M ;
Pallotti, F ;
Barrientos, A ;
Gajewski, CD ;
Kwong, JQ ;
Bruno, C ;
Beal, MF ;
Manfredi, G .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (50) :46925-46932