It is a textbook definition that in the absence of oxygen or inhibition of the mitochondrial
respiratory chain by pharmacologic or genetic means, hyper-reduction of the matrix
pyridine nucleotide pool ensues due to impairment of complex I oxidizing NADH, leading
to reductive stress. However, even under these conditions, the ketoglutarate dehydrogenase
complex (KGDHC) is known to provide succinyl-CoA to succinyl-CoA ligase, thus supporting
mitochondrial substrate-level phosphorylation (mSLP). Mindful that KGDHC is dependent
on provision of NAD+, hereby sources of acute NADH oxidation are reviewed, namely
i) mitochondrial diaphorases, ii) reversal of mitochondrial malate dehydrogenase,
iii) reversal of the mitochondrial isocitrate dehydrogenase as it occurs under acidic
conditions, iv) residual complex I activity and v) reverse operation of the malate-aspartate
shuttle. The concept of NAD+ import through the inner mitochondrial membrane as well
as artificial means of manipulating matrix NAD+/NADH are also discussed. Understanding
the above mechanisms providing NAD+ to KGDHC thus supporting mSLP may assist in dampening
mitochondrial dysfunction underlying neurological disorders encompassing impairment
of the electron transport chain.
