Thread by @lydfinley

Speaking of NAD/NADH (aren't we always?), time to revisit an ultimate #metabolismclassic while I sit at an airport gate: here, a deep dive from Krebs and colleagues dissecting the drivers and implications of the redox ratio in the cytosol and mitochondria pubmed.ncbi.nlm.nih.gov/4291787/

First, the premise: understanding the NAD/NADH ratio gives critical insight into what substrates are consumed and why, but it’s not trivial to directly measure these ratios

Next, the demonstration that the NAD/NADH ratio is not the same in the cyto and mito, and that these ratios do not travel together in disease states; broadly, the mito is more reduced than the cytosol

Then, lots of fun discussion. Why is it important the the mito remain more reduced? (Answer, preserve free-energy change of electron transfer from NADH to flavoprotein)

Also some important caveats: when can we use these ratios to infer compartment redox state?

Plus a reminder that free and bound NAD/NADH can provide very different values

This paper is full of other nuggets: discussion of whether GDH forms a transhydrogenase system, speculation on role of Pi and NH4+ in redox control, and a biochemical explanation for why mitochondria maintain a more reduced state compared to the cytosol. A truly great read!