A patient walks into the office that has a thyroid issue and menstruates for 10 days straight. Why does she experience fatigue relate this to the Electron Transport chain?

A patient walks into the office that has a thyroid issue and menstruates for 10 days straight. Why does she experience fatigue relate this to the Electron Transport chain?

Thyroid disease can impact the menstrual cycle and cause excessive menstruation (4). As we know, menorrhagia or heavy menstrual bleeding can result in anemia and reduce the amount of oxygen delivered to the tissues. Oxygen is essential to the Electron Transport Chain (ETC) as it is the final acceptor of hydrogen atom that allows for energy production, or ATP, in the mitochondria (see below). Plausibly, reduced energy production results in feeling of fatigue.

More about the ETC: The electron transport chain is a key piece of the process of oxidative phosphorylation and the point where most metabolic energy is released from catabolism of acetyl-coA (1).

Details of this process include the following (1):

To understand the ETC, the basics of oxidation-reduction potential must be understood. First remember the mnemonic OIL RIG = Oxidation Is Losing (an electron or hydrogen) and Reduction Is Gaining (an electron). The tendency for a molecule to not want to give or receive an electron is given a redox potential value of 0. Those molecules, like NADH, that want to give away the electron are given redox values in negative numbers with NADH = -320 mV. Those molecules like O2 that want electrons are given redox values that are positive numbness with O2 = +820 mV.

In the ETC, starting with NADH, there are progressive increases in the redox potential with each carrier molecule that the electron is passed to. Here is a diagram showing this redox potential increasing down the ETC with last acceptor being O2 molecule:

So, the NADH loses its hydrogen which consists of 1 electron and 1 proton – in this process NADH releases the electron of the hydrogen atom to the 1^st carrier molecules in the ETC and the photon is released to the mitochondrial matrix to be pumped across the mitochondrial membrane. Each carrier protein extends through the inner mitochondrial membrane. Since the membrane is impermeable to protons, the protons need to be pumped out of the matrix in order to achieve a Proton Gradient. With each increase in redox potential, the molecule can harness the energy to fuel the pumping out of protons. The proton gradient that results is used by ATP Synthetase molecule in the membrane to catalyze the addition of a phosphate to ADP making ATP.

One of the reasons for the complexity of this reducing process is (a) to harness the energy, and (b) to protect the cell from massive increase in energy. The process of combining free Hydrogen with Free Oxygen results in a large release of energy equivalent to 820 mV. This reaction is one of the largest in the human body (5). See this video for a demonstration of the energy that is released! https://youtu.be/hm9me9i13Q8

Key points (1):

• The Proton Gradient stores the energy of water formation and is usually 200 mV (or -1 pH unit). When the Gradient is too “large”, the ETC slows down. In other words, there is Respiratory Control on the ETC by the Proton Gradient. If you experimentally create an unusually large Proton Gradient, the ETC will stop and in some cases, there is leakage of the Gradient backwards to relieve pressure of the stored energy
• An Uncoupler is a molecule that removes the Respiratory Control of the Proton Gradient by binding to the Proton instead of allowing the Proton to move across the membrane. This also blocks ATP production AND creates heat.
• Brown Fat Cells naturally uncouple the mitochondria from ATP production and are a source of heat when needed. (This brings into view a possible function of ATP as a protective agent against cell “overheating”, also 2,3).
• Cyanide binds the last complex in the ETC blocking all electron transport
•  Omega6 FAs appear to interfere with uncoupling: “dietary excess of ω6 polyunsaturated fatty acids present in Western diets, may also favor obesity by preventing the “browning” process to take place” (8).

Finally, a review of thyroid mechanisms on the ETC (6): thyroid is known to regulate the metabolic rate and paradoxically is well known to reduce metabolic efficiency. In the 1950s it was shown that thyrotoxicosis in rats lead to reduced ATP production even while oxygen consumption increases. Given that thyroid replacement takes several days to show this effect, likely this is mediated through the thyroid hormone receptor which influences gene transcription. However, thyroid hormone is also suspected to play a role in promoting uncoupling (7).

What are the benefits of uncoupling that would be lost in hypothyroidism: “most evidence supports a role for mild uncoupling in ROS attenuation, and also in maintaining nutrient and energy homeostasis, both of which are likely important for optimizing lifespan.” For our patient in the case, uncoupling appears to represent 30% of the basal metabolic rate (9), so this is likely cause of fatigue as well as anemia.

Sources:

1/ Alberts B et al. Molecular Biology of The Cell, 2^nd Ed. Garland Publishing. 1989.

2/Madhusoodanan J.  Journal Club: ATP could help proteins dissolve in cells, prompting a rethink about its function and evolution. PNAS. 5/27/2017.

http://blog.pnas.org/2017/05/journal-club-atp-could-help-proteins-dissolve-in-cells-prompting-a-rethink-about-its-function-and-evolution/

3/ Ling G. OXIDATIVE PHOSPHORYLATION AND MITOCHONDRIAL PHYSIOLOGY: A CRITICAL REVIEW OF  HEMIOSMOTIC THEORY, AND REINTERPRETATION BY THE ASSOCIATION-INDUCTION HYPOTHESIS. Physiol Chem & Physics. (13). 1981.

http://www.gilbertling.org/PCP13-29_ling.pdf

4/ Briden L. What your period is trying to tell you about your thyroid? Menstruation Matters. 2/26/2016.

https://www.menstruationresearch.org/2016/02/26/what-your-period-is-trying-to-tell-you-about-your-thyroid/

5/ http://book.bionumbers.org/what-is-the-redox-potential-of-a-cell/

6/ Reitman ML. Thyroid hormone and other regulators of uncoupling proteins.  International Journal of Obesity (1999) 23, Suppl 6, S56±S59.
7/ Harper, M.-E., Seifert, E.L., 2008. Thyroid Hormone Effects on Mitochondrial Energetics. Thyroid 18, 145–156. https://doi.org/10.1089/thy.2007.0250
8/ Pisani, D.F., Ghandour, R.A., Beranger, G.E., Le Faouder, P., Chambard, J.-C., Giroud, M., Vegiopoulos, A., Djedaini, M., Bertrand-Michel, J., Tauc, M., Herzig, S., Langin, D., Ailhaud, G., Duranton, C., Amri, E.-Z., 2014. The ω6-fatty acid, arachidonic acid, regulates the conversion of white to brite adipocyte through a prostaglandin/calcium mediated pathway. Mol Metab 3, 834–847. https://doi.org/10.1016/j.molmet.2014.09.003
9/ Mookerjee, S.A., Divakaruni, A.S., Jastroch, M., Brand, M.D., 2010. Mitochondrial uncoupling and lifespan. Mechanisms of Ageing and Development 131, 463–472. https://doi.org/10.1016/j.mad.2010.03.010