In:
The FEBS Journal, Wiley, Vol. 280, No. 20 ( 2013-10), p. 5080-5093
Abstract:
Steadily growing experimental evidence suggests that mitochondrial dysfunction plays a key role in the age‐dependent impairment of nerve cells underlying several neurodegenerative diseases. In particular, the citric acid cycle enzyme complex α‐ketoglutarate dehydrogenase ( KGDHC ) and respiratory chain complex I of the respiratory chain often show reduced activities in the dopaminergic neurons involved in Parkinson's disease, both giving rise to an impaired mitochondrial energy metabolism as demonstrated in a number of in vitro studies with cell lines as well as isolated mitochondria. To understand the metabolic regulation underlying these experimental findings we used a detailed kinetic model of mitochondrial energy metabolism. First, we investigated the effect of complex I inhibition on energy production and formation of reactive oxygen species ( ROS ). Next, we applied the model to a situation where both KGDHC and complex I exhibit reduced activities. These calculations reveal synergistic effects with respect to the energy metabolism but antagonistic effects with respect to ROS formation: the drop in the ATP production capacity is more pronounced than at inhibition of either enzyme complex alone. Interestingly, however, the reduction state of the ROS ‐generating sites of the impaired complex I becomes significantly lowered if additionally the activity of the KGDHC is reduced. We discuss the pathophysiological consequences of these intriguing findings.
Type of Medium:
Online Resource
ISSN:
1742-464X
,
1742-4658
DOI:
10.1111/febs.2013.280.issue-20
Language:
English
Publisher:
Wiley
Publication Date:
2013
detail.hit.zdb_id:
2172518-4
SSG:
12
