Abstract
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 α-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.
Highlights
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
Mice lacking functional HtrA2 and cells derived from them show impaired mitochondrial function,[2,5] and Drosophila lacking HtrA2 were found to exhibit increased numbers of defective mitochondria,[6] all suggesting a crucial role for HtrA2 in maintaining mitochondrial physiology
Using tetramethylrhodamine methylester (TMRM) as a fluorescent indicator of decreased mitochondrial membrane potential (DCm), we found that HtrA2 deficiency induced a significant decrease in basal DCm in all primary cell types studied (Figure 1a)
Summary
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. HtrA2-KO mice exhibit decreased mitochondrial membrane potential (DCm) but increased mitochondrial respiration, suggesting severe uncoupling of oxidative phosphorylation They further show increased hyperpolarisation in response to oligomycin but decreased ATP production by the ATP synthase, suggesting that the proton leak occurs through the ATP synthase itself, indicating a novel role for HtrA2 in the maintenance of this protein complex. This uncoupling in turn leads to an alteration in breathing pattern in vivo, cellular
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