Oxaloacetate inhibition of succinate dehydrogenase: mechanism and physiological implications

As has been known for many decades, oxaloacetate (OAA) is a very potent inhibitor of succinate dehydrogenase (SDH). However, the phenomenon has received little attention for several reasons to be discussed. Although the interaction between OAA and the structure of SDH has been scrutinized, there has been little attention to the mechanism underlying OAA inhibition of SDH in respiring mitochondria or to its functional implications. In recent years, we have used more advanced methodology to examine these issues. OAA is unstable and therefore very difficult to detect by mass spectroscopy. Hence, we used a novel NMR approach to assess OAA in mitochondria of muscle, brown adipose tissue, and liver under active respiratory conditions. We also used a modification of existing technology to assess mitochondrial respiration in states apart from the extremes of state 4 and state 3. We found strong evidence that mitochondrial OAA content and inhibition of SDH are dependent on inner mitochondrial membrane potential (ΔΨ) and the effects of ΔΨ on the NADH/NAD⁺ redox state. Furthermore, we examined the effects of perturbed OAA content by deleting glutamic-oxaloacetic transaminase, which metabolizes OAA and glutamate to aspartate and α-ketoglutarate. Such deletion enhanced mitochondrial OAA and impaired metabolism through SDH. Here, we review historical and recent studies addressing OAA inhibition of SDH. We also discuss the possible physiological role of OAA/SDH interaction and whole-body consequences. Furthermore, we describe a novel methodology for the detection of OAA and assessment of mitochondrial function under conditions of clamped mitochondrial inner membrane potential.