I have been considering a hypothesis that PEM is actually a type of axon damage in the brain due to either a lack of NAD or an inability to change NMN to NAD. Axons are the long part of the nerve that runs from one synapse to the next, sort of the telephone wire of the nerve that the signals run through. Damage to axons has been found to be associated with ME/CFS, and damage to the axons has been found when nicotinamide mononucleotide (NMN) builds up due to insufficient activity of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) (but no one is connecting those two ideas, until now, as far as I know). So I am hypothesizing that the inhibition of the electron transport causes the lack of available ATP (which is one of the substrates of NMNAT) during periods of mental or physical activity leads to a buildup of NMN in the neurons, which damages the axons. Perhaps PEM is a temporary manifestation of the damage but by repeating the process which leads to PEM and not allowing for enough healing the damage can become worse and worse. By taking time out for complete rest periods you allow your body and brain to decrease the buildup of NMN in the neurons because the ATP can be shunted over to NMNAT during the rest periods, and this avoids the damaging PEM. Of course this is just a hypothesis and I don’t have any idea if it is correct but I think it has some interesting aspects.