The possible role of cytochrome c oxidase in stress-induced apoptosis and degenerative diseases


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I'm too brainfogged to really make sense of it, but a few aspects make me think it at least might be part of ME. T2 (3-5 diiodothyronine) had a significant and reliable effect on my ME symptoms, so I occasionally search for new papers about that, or search with new other terms. This paper came up, linking T2 with mitochondria.

Apoptotic cell death can occur by two different pathways. Type 1 is initiated by the activation of death receptors (Fas, TNF-receptor-family) on the plasma membrane followed by activation of caspase 8. Type 2 involves changes in mitochondrial integrity initiated by various effectors like Ca2+, reactive oxygen species (ROS), Bax, or ceramide, leading to the release of cytochrome c and activation of caspase 9. The release of cytochrome c is followed by a decrease of the mitochondrial membrane potential ΔΨm. Recent publications have demonstrated, however, that induction of apoptosis by various effectors involves primarily a transient increase of ΔΨm for unknown reason. Here we propose a new mechanism for the increased ΔΨm based on experiments on the allosteric ATP-inhibition of cytochrome c oxidase at high matrix ATP/ADP ratios, which was concluded to maintain low levels of ΔΨm in vivo under relaxed conditions. This regulatory mechanism is based on the potential-dependency of the ATP synthase, which has maximal activity at ΔΨm=100–120 mV. The mechanism is turned off either through calcium-activated dephosphorylation of cytochrome c oxidase or by 3,5-diiodo-l-thyronine, palmitate, and probably other so far unknown effectors. Consequently, energy metabolism changes to an excited state. We propose that this change causes an increase in ΔΨm, a condition for the formation of ROS and induction of apoptosis."

I'm posting this mainly because new discoveries often come from putting together concepts from different sources. This paper involves changes in ATP levels (from exertion?) with cell death (that'll mess up energy production). I reacted positively to T2 and negatively to palmitate.

This caught my attention too:

"The superoxide radical anion is only produced at higher membrane potentials (ΔΨm>140 mV) [34], [35], but not in mitochondria of resting cells, which posses a low ΔΨm. The regulation of the ΔΨm level in living cells, however, is not completely understood."

Something from exertion triggers PEM. Could this be an explanation? Could this level of cell death go unnoticed in ME/PEM studies while still causing serious symptoms?

Figuring this out is way beyond my education level (and I'm brainfogged in), but I thought it was thought-provoking enough to be worth posting.