Journal
CELL DEATH & DISEASE
Volume 3, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2012.77
Keywords
HtrA2; mitochondria; uncoupling; ATP synthase
Categories
Funding
- Medical Research Council [G0700183]
- Brain Research Trust (BRT)
- European Union
- Wellcome/MRC Parkinson's Disease Consortium
- University of Sheffield
- MRC Protein Phosphorylation Unit at the University of Dundee [WT089698]
- BBSRC
- Central Research Fund
- Bloomsbury Colleges Consortium
- PetPlan Charity
- RVC Internal Funds
- PDS
- Wellcome Trust
- Biotechnology and Biological Sciences Research Council [BB/I013695/1] Funding Source: researchfish
- Medical Research Council [G0700183, MC_G1000735] Funding Source: researchfish
- Parkinson's UK [F-0806] Funding Source: researchfish
- BBSRC [BB/I013695/1] Funding Source: UKRI
- MRC [G0700183, MC_G1000735] Funding Source: UKRI
Ask authors/readers for more resources
Loss of the mitochondrial protease HtrA2 (Omi) in mice leads to mitochondrial dysfunction, neurodegeneration and premature death, but the mechanism underlying this pathology remains unclear. Using primary cultures from wild-type and HtrA2-knockout mice, we find that HtrA2 deficiency significantly reduces mitochondrial membrane potential in a range of cell types. This depolarisation was found to result from mitochondrial uncoupling, as mitochondrial respiration was increased in HtrA2-deficient cells and respiratory control ratio was dramatically reduced. HtrA2-knockout cells exhibit increased proton translocation through the ATP synthase, in combination with decreased ATP production and truncation of the F1 alpha-subunit, suggesting the ATP synthase as the source of the proton leak. Uncoupling in the HtrA2-deficient mice is accompanied by altered breathing pattern and, on a cellular level, ATP depletion and vulnerability to chemical ischaemia. We propose that this vulnerability may ultimately cause the neurodegeneration observed in these mice. Cell Death and Disease (2012) 3, e335; doi:10.1038/cddis.2012.77; published online 28 June 2012
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available