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Human Molecular Genetics Advance Access originally published online on June 1, 2006
Human Molecular Genetics 2006 15(13):2157-2169; doi:10.1093/hmg/ddl141
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Marilena D'Aurelio1, Carl D. Gajewski1, Giorgio Lenaz2 and Giovanni Manfredi1,*

1 Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA and 2 Dipartimento di Biochimica, G. Moruzzi, Universitá di Bologna, Bologna 40126, Italy

* To whom correspondence should be addressed at: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 E. 68th Street, A-505, New York, NY 10021, USA. Tel: , +1 2127464605; fax: +1 212 7468276; Email: gim2004{at}mail.med.cornell.edu

Received April 26, 2006; Accepted May 24, 2006

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.


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