Novel biomarkers of mitochondrial dysfunction in Long COVID patients, 2024, Szögi et al.

[SNT Gatchaman]

Novel biomarkers of mitochondrial dysfunction in Long COVID patients
Szögi, Titanilla; Borsos, Barbara N.; Masic, Dejana; Radics, Bence; Bella, Zsolt; Bánfi, Andrea; Ördög, Nóra; Zsiros, Csenge; Kiricsi, Ágnes; Pankotai-Bodó, Gabriella; Kovács, Ágnes; Paróczai, Dóra; Botkáné, Andrea Lugosi; Kajtár, Béla; Sükösd, Farkas; Lehoczki, Andrea; Polgár, Tamás; Letoha, Annamária; Pankotai, Tibor; Tiszlavicz, László

Coronavirus disease 2019 (COVID-19) can lead to severe acute respiratory syndrome, and while most individuals recover within weeks, approximately 30–40% experience persistent symptoms collectively known as Long COVID, post-COVID-19 syndrome, or post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC). These enduring symptoms, including fatigue, respiratory difficulties, body pain, short-term memory loss, concentration issues, and sleep disturbances, can persist for months. According to recent studies, SARS-CoV-2 infection causes prolonged disruptions in mitochondrial function, significantly altering cellular energy metabolism.

Our research employed transmission electron microscopy to reveal distinct mitochondrial structural abnormalities in Long COVID patients, notably including significant swelling, disrupted cristae, and an overall irregular morphology, which collectively indicates severe mitochondrial distress. We noted increased levels of superoxide dismutase 1 which signals oxidative stress and elevated autophagy-related 4B cysteine peptidase levels, indicating disruptions in mitophagy. Importantly, our analysis also identified reduced levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in these patients, serving as a novel biomarker for the condition.

These findings underscore the crucial role of persistent mitochondrial dysfunction in the pathogenesis of Long COVID. Further exploration of the cellular and molecular mechanisms underlying post-viral mitochondrial dysfunction is critical, particularly to understand the roles of autoimmune reactions and the reactivation of latent viruses in perpetuating these conditions. This comprehensive understanding could pave the way for targeted therapeutic interventions designed to alleviate the chronic impacts of Long COVID. By utilizing circulating ccf-mtDNA and other novel mitochondrial biomarkers, we can enhance our diagnostic capabilities and improve the management of this complex syndrome.

Link | PDF (GeroScience)

 

[Murph]

Me a few years ago, naive: Novel biomarkers, YES!

Me now, jaded: novel biomarkers, UGH.

Nobody ever follows up some random lab's weird expensive technique.

 

[Hutan]

A team from Hungary:
Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary

Their hypothesis:

Mitochondria, essential for energy production and cellular metabolism, are particularly vulnerable to SARS-CoV-2 infection [36]. The virus may hijack and reprogram mitochondrial function or inflict direct damage through various mechanisms during and potentially after infection [36]. Such disruptions lead to altered energy metabolism, which is believed to contribute to the fatigue, cognitive impairments, and muscular weaknesses commonly observed in Long COVID patients [35, 36].

They looked at:

• nasal and bronchial samples - mitochondria visualised with transmission electron microscopy
• levels of proteins crucial to mitochondrial dynamics—specifically autophagy-related 4B cysteine peptidase (ATG4B), mitofusin 2 (MFN2), and dynamin-related protein 1 (DRP1)
• superoxide dismutase 1 (SOD1) protein levels - to assess oxidative stress status
• circulating cell-free mitochondrial DNA (ccf-mtDNA) in blood plasma to evaluate the integrity and functionality of mitochondrial recycling processes

 

[Hutan]

Electron microscopy of mitochondria

nasal mucosal and bronchial biopsy samples were collected from five PC patients (median age 28 years) and five controls who exhibited no post-COVID-19 symptoms but were diagnosed with secondary ciliary dyskinesia (median age 10 years). The primary symptoms of PC patients were smell disorders—anosmia, hyposmia, and dysosmia. Other reported symptoms included taste disorders—ageusia, hypogeusia, and dysgeusia—fatigue, and various respiratory conditions

So:

• small numbers of samples,
• controls not well matched (very different ages, and the controls aren't healthy controls,
• post-Covid symptoms of the Long Covid group are primarily olfactory problems, so not very relevant to ME/CFS

Unfortunately, I think all those problems add up to any findings not being very helpful, at least from our perspective.

TEM analysis revealed distorted mitochondrial integrity in PC patients, characterized by dilated and washed-out cristae and enlarged mitochondria compared to controls.

 

[Wyva]

An article was published about this study, with one of the researchers speaking about it. The article is kind of self-congratulatory, also, they are developing a test. No mention of ME/CFS or PEM or similar. I asked ChatGPT to translate:

A groundbreaking long-Covid study has been conducted at the University of Szeged.

This is one of the first studies to describe the morphological issues and the symptom cluster associated with long-Covid. Moreover, the researchers have laid the groundwork for a test based on blood serum that can indicate the severity of the disease. We spoke with Dr. Tibor Pankotai, one of the authors of the paper.

The coronavirus pandemic can lead to severe acute respiratory syndrome, and while most of us recover(ed) within weeks, approximately 30-40% of patients may experience persistent symptoms, such as shortness of breath, joint pain, sleep disturbances, mood swings, or cognitive impairments. Collectively, these are referred to as the long-Covid syndrome.

As previously reported, researchers had believed that those suffering from long-term symptoms of the disease would need to endure a recovery period of between 6 months and 3 years. According to an earlier British study, one-third of individuals with symptoms lasting 12 weeks recovered within a year. However, other studies, particularly among patients who required hospitalization, have shown significantly lower recovery rates.

A recent study published in GeroScience found that long-Covid causes prolonged disruptions in mitochondrial function, significantly altering the energy metabolism of cells. We spoke with Dr. Tibor Pankotai, one of the authors of the article, who is the head of the Genomic Integrity and DNA Repair Research Group at the Hungarian Centre of Excellence for Molecular Medicine (HCEMM) and a researcher at the Institute of Pathology at the University of Szeged, about:

• How the research was conducted
• The difference between post-Covid and long-Covid
• What makes the study unique
• Whether lifestyle factors are connected to the coronavirus
• Potential treatment paths

Six Months as the Critical Threshold
The study employed transmission electron microscopy to investigate mitochondrial structural abnormalities in long-Covid patients and detect whether oxidative stress was present (it was). Their analysis confirmed the presence of persistent mitochondrial dysfunction in patients suffering from long-Covid.

Chest pain and loss of smell persisting 10–12 weeks after acute infection are classified as post-Covid, whereas long-Covid refers to symptoms that persist for a longer period. Dr. Tibor Pankotai explains that symptoms lasting 3 to 6 months are termed post-Covid, and beyond that, the correct term is long-Covid. However, the terminology is often confused in public discourse.

"Our study is important because knowledge about what causes long-Covid symptoms has been very limited. This article provides the first comprehensive summary suggesting that the lingering symptoms may have a cellular biological cause.

With this new understanding, we can now focus on questions of reversibility and the use of mitochondrial regenerative agents," Pankotai says. These agents are typically known from anti-aging research, such as coenzyme Q10. "These substances act on the cells, activating restorative mechanisms. This is what needs to happen in post-Covid as well. In long-Covid, this restorative process doesn’t function properly, but medications can help restart it."

He compares the effect of the coronavirus on mitochondria to a hacker stealing money from a bank account: "It reprograms the body, forcing those affected to live with a rewired system."

Lifestyle Matters More Than Age
When asked whether age affects how long symptoms persist, Pankotai responds that lifestyle plays a more significant role. "Overweight individuals experience slower recovery, although genetic predisposition can also influence the severity and duration of an infection. In overweight patients, autophagy (the self-cleaning and self-renewal process of cells) is slower and less effective, hindering protein recycling. For individuals with a normal weight, this process works perfectly, leading to quicker recovery. So, lifestyle, rather than age, is a key factor."

About the Study
Patients from the University of Szeged’s Pulmonology, Otolaryngology, and Infectious Diseases Clinics participated in the study. These were patients who had received acute care, provided blood samples, and some underwent lung biopsies. Unfortunately, the study could not determine the efficacy of vaccines because most participants had been sick for 2.5–3 years, predating vaccine availability.

Dr. Pankotai shares that additional studies are now underway, funded by grants from the Hungarian Academy of Sciences (MTA) focusing on post-coronavirus symptoms.

"We are still at the beginning stages of descriptive studies, but ours is one of the first to outline the morphological problems and symptom clusters. In the second half of the study, we also laid the foundation for a test based on blood serum, which could be used to monitor the severity of long-Covid."

The severity of long-Covid symptoms correlates with the amount of mitochondrial DNA in the serum. Patients with long-Covid have significantly reduced levels, which could serve as the basis for a test to identify prolonged Covid and determine the severity of the condition.

"We’ve already filed two patents and will next explore how to reverse the lingering symptoms of the disease. We’ll also investigate how dietary supplements—like Q10—can strengthen the body and address mitochondrial issues caused by long-Covid."