Stepanova 2016 Biochim Biophys Acta

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Stepanova A, Shurubor Y, Valsecchi F, Manfredi G, Galkin A (2016) Differential susceptibility of mitochondrial complex II to inhibition by oxaloacetate in brain and heart. Biochim Biophys Acta 1857:1561-8.

» PMID: 27287543 Open Access

Stepanova A, Shurubor Y, Valsecchi F, Manfredi G, Galkin A (2016) Biochim Biophys Acta

Abstract: Mitochondrial Complex II is a key mitochondrial enzyme connecting the tricarboxylic acid (TCA) cycle and the electron transport chain. Studies of complex II are clinically important since new roles for this enzyme have recently emerged in cell signalling, cancer biology, immune response and neurodegeneration. Oxaloacetate (OAA) is an intermediate of the TCA cycle and at the same time is an inhibitor of complex II with high affinity (Kd~10-8M). Whether or not OAA inhibition of complex II is a physiologically relevant process is a significant, but still controversial topic. We found that complex II from mouse heart and brain tissue has similar affinity to OAA and that only a fraction of the enzyme in isolated mitochondrial membranes (30.2±6.0% and 56.4±5.6% in the heart and brain, respectively) is in the free, active form. Since OAA could bind to complex II during isolation, we established a novel approach to deplete OAA in the homogenates at the early stages of isolation. In heart, this treatment significantly increased the fraction of free enzyme, indicating that OAA binds to complex II during isolation. In brain the OAA-depleting system did not significantly change the amount of free enzyme, indicating that a large fraction of complex II is already in the OAA-bound inactive form. Furthermore, short-term ischemia resulted in a dramatic decline of OAA in tissues, but it did not change the amount of free complex II. Our data show that in brain OAA is an endogenous effector of complex II, potentially capable of modulating the activity of the enzyme.

Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Keywords: Ischemia, Krebs cycle, Mitochondrial complex II, Oxaloacetate, Succinate dehydrogenase

O2k-Network Lab: UK Belfast Galkin A, US NY New York Galkin A


Labels: MiParea: Respiration 


Organism: Mouse  Tissue;cell: Heart, Nervous system  Preparation: Oxidase;biochemical oxidation  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase  Regulation: Inhibitor 

Pathway:HRR: Oxygraph-2k 

2016-07