Journal
FASEB JOURNAL
Volume 30, Issue 6, Pages 2236-2248Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201500137R
Keywords
blue native PAGE; oxidative phosphorylation; respiratory chain; supercomplex
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Funding
- Poxon Neurosurgical Foundation
- Australian National Health and Medical Research Council [APP1061472]
- Wagstaff Bequest of the Royal Victorian Eye and Ear Hospital
- Australian Research Council
- William Buckland Foundation
- Monash University
- Group of Eight Fellowship
- Czech Republic award [PRVOUK-P26/LF1/4]
- Victorian Government Infrastructure Program
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Mitochondrial complex I (NADH:ubiquinone oxidoreductase) must be assembled precisely from 45 protein subunits for it to function correctly. One of its mitochondrial DNA (mtDNA) encoded subunits, ND1, is incorporated during the early stages of complex I assembly. However, little is known about how mutations in ND1 affect this assembly process. We found that in human 143B cybrid cells carrying a homoplasmic MT-ND1 mutation, ND1 protein could not be translated. As a result, the early stages of complex I assembly were disrupted, with mature complex I undetectable and complex I-linked respiration severely reduced to 2.0% of control levels. Interestingly, complex IV (ferrocytochrome c:oxygen oxidoreductase) steady-state levels were also reduced to 40.3%, possibly due to its diminished stability in the absence of respiratory supercomplex formation. This was in comparison with 143B cybrid controls (that contained wild-type mtDNA on the same nuclear background), which exhibited normal complex I, complex IV, and supercomplex assembly. We conclude that the loss of ND1 stalls complex I assembly during the early stages of its biogenesis, which not only results in the loss of mature complex I but also disrupts the stability of complex IV and the respiratory supercomplex to cause mitochondrial dysfunction.Lim, S. C., Hroudova, J., Van Bergen, N. J., Lopez Sanchez, M. I. G., Trounce, I. A., McKenzie, M. Loss of mitochondrial DNA-encoded protein ND1 results in disruption of complex I biogenesis during early stages of assembly.
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