Stepanova 2017 J Cereb Blood Flow Metab
|Stepanova A, Kahl A, Konrad C, Ten V, Starkov AS, Galkin A (2017) Reverse electron transfer results in a loss of flavin from mitochondrial complex I: Potential mechanism for brain ischemia-reperfusion injury. J Cereb Blood Flow Metab 37:3649-58.|
Abstract: Ischemic stroke is one of the most prevalent sources of disability in the world. The major brain tissue damage takes place upon the reperfusion of ischemic tissue. Energy failure due to alterations in mitochondrial metabolism and elevated production of reactive oxygen species (ROS) is one of the main causes of brain ischemia-reperfusion (IR) damage. Ischemia resulted in the accumulation of succinate in tissues, which favors the process of reverse electron transfer (RET) when a fraction of electrons derived from succinate is directed to mitochondrial complex I for the reduction of matrix NAD+. We demonstrate that in intact brain mitochondria oxidizing succinate, complex I became damaged and was not able to contribute to the physiological respiration. This process is associated with a decline in ROS release and a dissociation of the enzyme's flavin. This previously undescribed phenomenon represents the major molecular mechanism of injury in stroke and induction of oxidative stress after reperfusion. We also demonstrate that the origin of ROS during RET is flavin of mitochondrial complex I. Our study highlights a novel target for neuroprotection against IR brain injury and provides a sensitive biochemical marker for this process.
- Komlodi T et al (2021) Oxygen dependence of hydrogen peroxide production using Amplex UltraRed in yeast cells, isolated mitochondria, and permeabilized cells. MitoFit Preprints 2021 (in prep).
Labels: MiParea: Respiration
Stress:Ischemia-reperfusion Organism: Mouse Tissue;cell: Nervous system Preparation: Isolated mitochondria Enzyme: Complex I Regulation: Inhibitor Coupling state: LEAK, OXPHOS, ET Pathway: N, NS, ROX HRR: Oxygraph-2k, O2k-Fluorometer
2017-12, AmR, Tissue normoxia, MitoFit 2021 AmR