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  • Writer's pictureRob Swanda, PhD

Long Covid: Molecules & Mitochondria

September 18, 2022

Words & Video by Dr. Rob Swanda

While headlines across the world bolster about increased job growth recovery from 2020, a silent goliath is driving job loss. The United States (U.S.) Census Bureau added four questions to the 2022 household pulse survey about Long Covid. From the responses, they have estimated that more than 16 million Americans aged 18-65 have Long Covid right now. This data is supported by additional investigations from the Federal Reserve Bank of Minneapolis & a study in The Lancet, which estimated 17 million Americans have Long Covid. These staggering numbers furthermore estimate that 4-5 million of those with Long Covid are out of work due to their condition, while several million others have had to reduce their work hours. And, this is not confined to only the U.S. The Bank of England estimated that 1% of the entire workforce aged 16-64 is not working due to suspected Long Covid. Unfortunately, there are few clinics around the world that provide Long Covid support, and many physicians are still aiming to better understand the etiology of the condition. Last year, I talked with several Long Covid advocacy groups to bring awareness to the condition (read here). A year later and few questions have found their answers.

The Centers for Disease Control (CDC) and research studies classify Long Covid as a collection of related symptoms (most common: fatigue, brain fog, & memory difficulties) that persist beyond 28 days from an infection of SARS-CoV-2. Other symptoms may include shortness of breath, chest pain, joint aches, and sleep problems.

Figure 1: Symptoms of Long COVID
Figure 1: Symptoms of Long COVID

The estimates of Long Covid prevalence range from around 12-20% according to multiple studies. It’s still unknown why some individuals suffer from Long Covid, while others do not. Despite most questions left unanswered some research studies have begun to hit the surface of this complex condition.

Although the majority of Long Covid studies have had small sample sizes, they serve as a starting point to the search for answers. Various Long Covid support groups have also turned to research from other less studied conditions, such as chronic fatigue (ME/CFS) and/or fibromyalgia (FM). Chronic Fatigue is a disorder illustrated by extreme fatigue over a period of six or more months, and that cannot be justified by any underlying medical condition(s). Fibromyalgia is a condition that causes pain all over the body as well as sleep problems, fatigue, and often emotional and mental distress.

NIH RECOVER is investigating and funding further Long Covid studies, but minimal information has been identified or disclosed. Of the research that has been conducted so far, there are indicators which may warrant further investigation and clinical trials.

For two years, molecular biologists have aimed to identify a biomarker for Long Covid with the hopes that this would point to clarity on the mechanism of action to what leads to the condition. One overarching feature of various Long Covid studies (small & large) is a drop in a molecule known as cortisol. Cortisol is a hormone that cycles throughout the day and is closely linked with inflammation and the immune response. So, when cortisol levels are not in balance, inflammation and the immune response are not either (see Video: What is Cortisol?). This imbalance of the immune system is also observed in patients with Long Covid. For example, researchers have observed immune response markers in Long Covid patients that are typically associated with a heightened immune system activation (e.g.: infection).

Cortisol is also important for the HPA (hypothalamus – pituitary – adrenal) axis feedback loop. This axis is like a controller, which plays a critical part to turning on and off production of various hormones. It also acts as a built-in body clock, allowing the brain to sense and respond to cortisol in our blood, which further helps individuals wake-up and go to sleep.

Beyond the consistent drop in cortisol levels, it has also been documented that some Long Covid patients have had reactivation of dormant Epstein–Barr and varicella-zoster viruses, known to cause mononucleosis and herpes. The mechanisms of this viral-reactivation remain unclear. This unveils even more questions of what secondary and tertiary metabolites are being altered from Long Covid? Are these responsible for viral reactivation? Can researchers identify ways to halt viral reactivation?

While the drop in cortisol levels are an intriguing finding and may help to explain why Long Covid patients suffer chronic fatigue, other researchers have investigated the exact opposite, energy production, to better understand if prior Covid infections may be linked to reducing the body’s ability to produce and/or store energy.

Other advocacy groups, such as those for ME/CFS, have found striking similarities between that condition and Long Covid. Researchers have since turned to some of the studies on ME/CFS (despite the much needed increase of research in this field). One interesting connection is the impairment of an organelle inside our cells called the mitochondria. The mitochondria is responsible for producing a majority of the energy our cells need, and most cells have hundreds of mitochondria. But, with ME/CFS the mitochondria that are present in our cells do not work as efficiently, making less energy. This may be a factor in explaining the most common symptom of chronic fatigue. Right now, the functionality of the mitochondria is under investigation with Long Covid as well.

Figure 2: Cortisol and Mitochondria Explainer
Figure 2: Cortisol and Mitochondria Explainer

In one promising study, administering difference doses of oxaloacetate at varying times during the day found a reduction in fatigue on one-third of patients. Oxaloacetate is an intermediate molecule that the mitochondria needs to help make energy. While a larger, more robust clinical trial will be able to bolster these findings, unfortunately the price of the medication used is $500 or more per month. This will likely be out of reach for many sufferers of target conditions who may already be financially affected, under-employed, or even unemployed because of their debilitation. Taking into account a cost-efficient strategy is also key for delivering relief.

Despite oxaloacetate injections being just one small scale study, there are currently no validated therapies for treatment of Long Covid, only symptom management. Although symptom management can offer temporary relief, this can also come with side effects from various medications. This adds additional pressure for trials examining therapies to move quicker.

Having a comprehensive idea of what Long Covid does to the body will take collaborations across disciplines (medical & scientific) and will require more government funding. Additionally, various Long Covid advocacy groups are looking to sponsor research in this field. Reputable and reliable support for those with Long Covid is available as is the possibility to become involved in critical research. For support or to see if you are a candidate for research clinics, speak with your primary healthcare provider or reach out for help in finding support in your area.

Data sources:

Centers for Disease Control and Prevention. (2022, 08 17). Post-COVID Conditions.

Retrieved from Centers for Disease Control and Prevention:

Centers for Disease Control and Prevention. (2022, 06 22). Nearly One in Five American Adults Who Have Had COVID-19 Still Have "Long COVID".

Retrieved from Centers for Disease Control and Prevention:

Health Rising. (2022, 09 01). The Long-COVID Treatment Trials Thus Far: Winners, Losers and the In-Betweeners.

Retrieved from Health Rising:

The Brookings Institution. (2022, 08 24). New data shows long Covid is keeping as many as 4 million people out of work.

Retrieved from The Brookings Institution:


Author: Rob Swanda, PhD of

Title: Long Covid: Molecules & Mitochondria

Date first published: 18 September 2022

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