Thread by @PutrinoLab

Ok, so after that (unintentional) cliffhanger, let's talk about energy production infrastructure and post-exertional malaise (PEM) in people with infection- and exposure-associated chronic illnesses (IACIs) such as #LongCOVID, #MECFS, chronic #Lyme and more. Let's start with 1/

how cells produce energy. ATP is the body's energy currency, and we only know how to make this currency from glucose, so our bodies need to turn glucose into ATP. They can do so either aerobically (using oxygen and mitochondria) or anerobically (fast, but inefficient, no 2/

mitochondria). Energy is never free in this universe, so both processes produce both ATP and waste
- Aerobic: 36-38 ATP units per glucose unit, producing reactive oxygen species (ROSs) as waste
- Anerobic: 2 ATP units per glucose unit, producing pyruvate and lactate as waste
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Mitochondrial energy is our body's go-to, so dysfunction causes problems. Why are we having problems caused by IACIs?
1) Persistent pathogens, especially viruses: viruses hijack our mitochondria because they don't have their own (rude). So they infect our cells and use them to 4/

produce the energy necessary to replicate. We've all had this experience in acute illness: a viral illness takes us down, then we wake up one morning and feel pretty ok so we push ourselves, crash hard and experience a couple of days of extra illness because we went too hard 5/

too fast. Just like any self-respecting combustion engine, our mitochondria can only produce so much energy before they start to break down, get choked up with waste (ROSs) and start to push us into energy deficit, so if a persistent virus (or host of reactivated viruses) is 6/

making many of our mitochondria produce "energy for two", this is going to cause energetic problems
Targeted antivirals, monoclonals and combinations of monoclonals are the answer here but require careful and strategic research (see our recent paper!).
7/thelancet.com/journals/lanin…

In the meantime, mitochondrial support in the form of things like oxaloacetate, CoQ10, NAD+, mTOR inhibitors, creatine et al may be beneficial to explore in collaboration with your physician.
2) Chronic inflammation: Maybe your body clicked into a chronic inflammatory 8/

state and can't snap out of it? Maybe persistent pathogens are causing chronic inflammation or maybe something environmental (chemical exposure, mold, heavy metals) are keeping you in a chronic inflammatory state after an initial triggering event. Regardless of the cause, 9/

inflammation costs energy and, again, no matter how much I complain to management, in this universe, energy isn't free. So mitochondria need to work overtime. More energy spent creating an inflammatory response means less energy for exertion, and *dire* consequences 10/

(in the form of feeling literally poisoned by reactive oxygen species) if you push beyond that energy envelope.
3) Autoimmunity: Autoimmunity could most definitely be driving some of the symptom burden in a subset of folks with IACIs (see our paper).

11/medrxiv.org/content/10.110…

Autoimmunity leads to chronic inflammation, chronic inflammation is a total energy pig, and here we are again: producing way too much energy per mitochondrion, proliferation of ROSs, damaging mitochondria every time you push beyond your energy envelope and cause a crash. As 12/

we navigate potential cures for chronic inflammatory drivers (heavy metal chelation, mold removal, targeting persistent pathogens, IVIG and FcRn inhibitors for autoimmunity), and try out mitochondrial support strategies, we must also remember the magic word: PACING. If these 13/

mechanisms drive your PEM, pushing through until you crash is going to cause mitochondrial damage and worsening issues. Pacing is an energy management tool that can prevent this. I really love this video from @LongCOVIDPhysio describing pacing:

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but in addition to this, we have shown that folks who use technology-assisted pacing may experience an improvement in their ability to manage their energy, as well as identify biomarkers associated with triggering a crash:
researchgate.net/publication/38…

researchgate.net/publication/38…

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So we've talked about some of the ways that we can overwork mitochondria, but what if the mitochondria can't get what they need? Mitochondria need glucose and glucose gets to cells via vasculature. Whether it be due to viral antigens like circulating spike, or simply chronic 16/

inflammation causing excessive fibrinogen production, we now know thanks to work led by folks like @resiapretorius, @doctorasadkhan and @dbkell and now replicated by countless others, that IACIs can cause the proliferation of fibrin-rich, amyloid-containing particles (that 17/

the world has nicknamed 'microclots' - see our paper). These microclots can clog up microvasculature and cause all sorts of dysfunction, including inflammation, but also affecting our ability to adequately transport glucose and oxygen into cells for
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cell.com/trends/endocri…

our mitochondria. In addition, recent work has also shown that excess sodium and calcium in the intracellular environment is seen in #MECFS and #LongCOVID due to ion channel dysfunction (see paper!).

When too much calcium and potassium flood the 19/

onlinelibrary.wiley.com/doi/pdfdirect/…

intracellular environment it disrupts mitochondrial function and blocks the ability of the mitochondria to utilize oxygen efficiently, leading to ROS proliferation and PEM. Klaus Wirth and Carmen Scheibenbogen (and many others) are doing important work on this in Berlin. 20/

Finally, the incomparable @RobWust and his brilliant team are also starting to show morphological changes in microvasculature in #LongCOVID and #MECFS that would make it harder for resources to make it to the mitochondria. In a recent poster, they showed changes in vascular 21/

size and structure associated with ppl with #LongCOVID and pre-2020 #MECFS that were CLEARLY different from healthy controls. So. We have under-resourced and overworked, mitochondria - how would that manifest systemically? Well. Obviously, if we actually LISTENED to people, 22/

they would tell us that they have PEM. But also, if you did invasive CPET on them, you might notice that they show impaired oxygen extraction (resources can't get to the cells) when they exert themselves. Thanks for showing it beautifully, Dr Systrom:
23/sciencedirect.com/science/articl…

You might also see that when you force them to exercise, their body produces abnormal waste product associated with altered energy production that CANNOT be explained by deconditioning. Thanks for debunking that, @RobWust. And you might also see that

24/researchgate.net/publication/39…

when you push folks too hard, they have lactic acid build-up because they're now using anerobic energy production almost exclusively:

God. I'm out of space (and time) again, so:
1) QED: PEM is biological.
2) to my haters, see you in hell. ✌️
/endnature.com/articles/s4159…