Succinate in ischemia: Where does it come from?

During tissue ischemia succinate accumulates. Herein, literature spanning the past nine decades is reviewed leaning towards the far greater role of Krebs cycle's canonical activity yielding succinate through α-ketoglutarate -> succinyl-CoA -> succinate even in hypoxia, as opposed to reversal of succinate dehydrogenase. Furthermore, the concepts of i) a diode-like property of succinate dehydrogenase rendering it difficult to reverse, and ii) the absence of mammalian mitochondrial quinones exhibiting redox potentials in the [-60, -80] mV range needed for fumarate reduction, are discussed. Finally, it is emphasized that a "fumarate reductase" enzyme entity reducing fumarate to succinate found in some bacteria and lower eukaryotes remains to be discovered in mammalian mitochondria.