How Covid-19 Alters Energy Metabolism
COVID-19 interacts with metabolic disorders by altering energy metabolism
Has COVID sapped your energy? There is a reason for it.
COVID-19 alters energy metabolism by reprogramming amino acid, glucose, cholesterol, and fatty acid pathways (Sheng and Wang 2021). This changes how the body uses and makes energy. It can decrease energy production. Even worse, it increases inflammation, disrupts how the body manages calcium, and impairs immune functioning.
*Sam L (16 year old): "I'm just so tired of being tired all the time. I know many people have it much worse than me but I hate being exhausted 24/7, especially as a 16 year old it's just really hard to make friends when I can't even go to school most days. I have had to drop all my extracurriculars and I'm too tired to hang out with my friends."
Domenico Fetti - Sleeping Girl c1615 oil on canvas.
How the sneaky COVID-19 virus, SARS-CoV-2, targets energy metabolism
1) COVID-19 cripples mitochondria, the cell's energy plants
COVID-19 can cause sustained damage to energy production by crippling mitochondria all over the body (Guarnieri et al. 2023). Mitochondria make most of your energy. They have their own DNA which is separate from your other cells.
The COVID virus blocks the transcription (basically the ability to make new copies) of mitochondrial oxidative phosphorylation (OXPHOS) genes. Mitochondria make energy using oxidative phosphorylation. Up to 16% of the polyproteins the COVID virus binds to are mitochondrial proteins (discussion in Guarnieri et al. 2023). This means that COVID-19 has a huge effect on energy production.
OXPHOS mRNAs was reduced in the heart, liver, kidney, and lymph nodes in autopsy samples from people who died from COVID-19. The heart had the most coordinated lock down of OXPHOS gene expression with virtually all the genes shut down. Other genes involved in glycolysis and pentose phosphate pathway were also reduced. Lung samples showed an over production of OXPHOS genes (Guarnieri et al. 2023).
Blue Box of Science: Impairing OXPHOS genes impair mitochondria function in several ways.
1) It increases production of superoxide. This is partially due to less efficiency in transferring electrons through the electron transport chain. This increases the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which increases overall inflammation. ROS and RNS can also act as signaling messengers in protein function and cellular redox balance. Redox homeostasis, which is a balance between creating and eliminating ROS/RNS, helps maintain the proper function of redox-sensitive signaling proteins and makes sure cells respond properly to stimuli.
2) It disturbs ATP production and ATP/ADP homeostasis. ATP transfers energy around the body. When your body uses the energy stored in ATP it strips away a phosphate molecule. This releases the energy stored in the phosphate bond and turns ATP (Adenosine triphosphate) into ADP (Adenosine Diphosphate). Take away one more phosphate and you get AMP (adenosine monophosphate).
ADP (ADP + elemental phosphate = ATP) is commonly used as a signaling molecule. Think of it as an indicator that you are using energy. If you have too much or too little ATP compared to ADP your body tries to compensate. For example, extracellular ADP released from stressed cells unable to recycle ADP to ATP can prompt healthy cells to transfer their healthy mitochondria to the stressed out cells (Li et al. 2024). This can help increase overall energy.
3) It causes an influx of Ca2+ to pour into the cytoplasm, nucleus, and mitochondria. Since Ca2+ is used for cell signaling this disrupts cellular messaging. More specifically, it can disrupt the mitochondria inner membrane potential and cause the cell to kill itself by apoptosis.
4) Discussion in Reinecke et al. 2009, Guarnieri et al. 2023).
2) Infection by COVID-19 activates microRNA 2392.
MicroRNAs (miRNAs) are small non-coding RNAs. Non-coding means they do not make a protein. MiRNAs are involved in post-transcriptional gene regulation; this is when the RNA or DNA strand is changed to make it a functional protein. Some post-transcriptional modifications include RNA splicing: cutting out segments from the RNA and slicing the remaining parts back together; adding protective end caps to the stand to make it more stable; and MiRNA binding which can increase or decrease the strand stability. This can affect pathways that are related to viruses and diseases (Trobaugh and Klimstra 2016, McDonald et al. 2021).
Viruses can use MiRNA to complete their replication cycle (make more viruses) while sneakily avoiding the immune system.
COVID-19 virus increases the amount of MiRNA 2392 (miR-2392). As MiRNA 2392 increases it influenced other systems, including pathways that down regulate (inhibit) mitochondrial gene expression such as OXPHOS. This causes increased inflammation, more glycolysis (making energy from glucose), and hypoxia (low oxygen levels). It may also cause or worsen COVID-19 symptoms (discussion McDonald et al. 2021, Guarnieri et al. 2023). The resulting decrease in mitochondria energy output would have the adverse effect on areas that use the most energy such as brain, heart, and kidneys.
3) COVID-19 activates hypoxia-inducible factor (HIF-1a) which induces glycolysis
Low oxygen conditions (hypoxia), cancer, and viruses such as COVID-19 can activate hypoxia inducible factor-1a (HIF-1a). Upregulated HIF-1a can increase glycolysis at the expense of the citric acid cycle (also called tricarboxylic acid cycle (TCA) or Krebs Cycle). In glycolysis, a molecule of glucose from food is converted to two smaller sugar molecules (pyruvate), and nets 2 molecules of ATP. Glycolysis can function without oxygen.
Upregulating glycolysis fuels glycolytic side pathways that are crucial for an effective inflammatory response by influencing the cell's redox balance as well as by providing building blocks and substrates for epigenetic reprogramming
Want to know more and see diagrams? Check out Glycolysis on NIH.
4) COVID infection activates your immune defenses including the integrated stress response.
Coronavirus replication can activate endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Basically, when the ER gets stressed out it stops doing the job of making, folding, modifying and sorting proteins properly. UPR can influence major signaling pathways, including innate immunity, autophagy, apoptosis, the mitogen-activated protein (MAP) kinase pathways, and pro-inflammatory response. (Fung et al. 2014, Guarnieri et al. 2023).
5) COVID-19 targets amino acid production.
Amino acids make protein and are vital for building and repair. There is a lot of evidence that sicker and older people need more protein. See our pages on protein for more.
Blue Box of Science: amino acids pathways influenced by COVID-19
1) COVID-19 targets tryptophan pathways; tryptophan is an essential amino acids
✱ This increases kynurenine levels (too much kynurenine activates the immune system and increases neurotoxins)
✱ Decreases tryptophan, serotonin, and indolepyruvate levels
✱ This causes immune system suppression
✱ Almulla et al. 2024
2) Depletes arginine, a semi-essential amino acid
✱ This suppresses T-cells and influences endothelial function (endothelium cells line blood vessels)
✱ May need L-arginine supplemented in COVID-19
✱ A study of people with Long COVID (1,390 women and men) found that those who supplemented with L-Arginine and vitamin C for a month had significant improvements compared to an alternate group. They took 2 doses of L-Arginine (1.66 g) and 500 mg of liposomal Vitamin C. there were improvements in fatigue (asthenia), shortness of breath (dyspnea), chest tightness, dizziness, gastrointestinal disorders, headaches, loss of smell (anosmia), concentrating and sleeping (Izzo et al. 2022).
3) Decreases glutamine, a nonessential amino acid
✱ Viruses, including the COVID-19 virus SARS-CoV-2, increase glutamine metabolism to fuel viral replication
✱ This means there is less glutamine available to make glutamate
✱ Glutamate, cysteine, and glycine are used to make glutathione (GSH); it is used in antioxidant defense and cell proliferation
✱ Glutamine feeds into the TCA cycle to make energy and lipids; feeding glutamine into the TCA cycle is reduced in SARS-CoV-2 infection (so production of energy and lipids is reduced)
4) The lack of amino acids, such as L-carnitine, results in fatty acid transport dysfunction
✱ Carnitine is needed to transfer long-chain fatty acids across the inner mitochondrial membrane for β-oxidation (which makes energy)
✱ Without L-carnitine to carry fatty acids, you are not able to make as much energy
✱ Carnitine can be synthesized by your body or obtained from meat and dairy foods
✱ L-carnitine is also an immune regulator for proinflammatory cytokines like IL-6, IL-1, and TNF-α (Vaziri-Harami and Delkash 2022)
In oxidative phosphorylation, energy from the chemical bonds in food is collected as electrons and protons (protons are hydrogen atoms that have lost their electron). Electrons represent the stored energy in food; after being stripped from food they are attached to energy carrier molecules (such as NADH and FADH). Electrons are carried to and transported through the electron transport chain (ETC) in a series of redox reactions. The ETC uses the energy gained from flowing electrons to pump protons into a inner membrane space. This creates a electrochemical gradient (somewhat like a biochemical battery).
Mitochondria use this gradient to make ATP using a ATP synthase. Protons move from the crowded inner membrane space, through the ATP synthase, into a less crowded outer space. This causes the ATP synthesis to rotate like a water wheel. The mechanical energy generated by the ATP synthase spinning is used to squeeze ADP and phosphate together to regenerate ATP.
ATP contains three high energy phosphate bonds. Breaking one of those bonds releases energy for your body to use. When this happens, one phosphate is lost and ATP (adenosine triphosphate) becomes ADP (adenosine diphosphate).
Higher protein intake may be needed in people with Long COVID
As discussed above, Long COVID may impair the bodies ability to make some amino acids. One way to overcome this is to consume higher amounts of protein.
*Names and some minor identifying details in all stories in this website are changed to protect people's privacy.
This information is for informational purposes only and does not constitute medical advice, diagnosis, or treatment.
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