Persistent Monocytic Bioenergetic Impairment and Mitochondrial DNA Damage in PASC Patients with Cardiovascular Complications, 2025, Semo+

[SNT Gatchaman]

Persistent Monocytic Bioenergetic Impairment and Mitochondrial DNA Damage in PASC Patients with Cardiovascular Complications
Semo, Dilvin; Shomanova, Zornitsa; Sindermann, Jürgen; Mohr, Michael; Evers, Georg; Motloch, Lukas J.; Reinecke, Holger; Godfrey, Rinesh; Pistulli, Rudin

Cardiovascular complications are a hallmark of Post-Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection (PASC), yet the mechanisms driving persistent cardiac dysfunction remain poorly understood. Emerging evidence implicates mitochondrial dysfunction in immune cells as a key contributor. This study investigated whether CD14++ monocytes from long COVID patients exhibit bioenergetic impairment, mitochondrial DNA (mtDNA) damage, and defective oxidative stress adaptation, which may underlie cardiovascular symptoms in PASC.

CD14++ monocytes were isolated from 14 long COVID patients with cardiovascular symptoms (e.g., dyspnea, angina) and 10 age-matched controls with similar cardiovascular risk profiles. Mitochondrial function was assessed using a Seahorse Agilent Analyzer under basal conditions and after oxidative stress induction with buthionine sulfoximine (BSO). Mitochondrial membrane potential was measured via Tetramethylrhodamine Ethyl Ester (TMRE) assay, mtDNA integrity via qPCR, and reactive oxygen species (ROS) dynamics via Fluorescence-Activated Cell Sorting (FACS). Parallel experiments exposed healthy monocytes to SARS-CoV-2 spike protein to evaluate direct viral effects. CD14++ monocytes from long COVID patients with cardiovascular symptoms (n = 14) exhibited profound mitochondrial dysfunction compared to age-matched controls (n = 10).

Under oxidative stress induced by buthionine sulfoximine (BSO), long COVID monocytes failed to upregulate basal respiration (9.5 vs. 30.4 pmol/min in controls, p = 0.0043), showed a 65% reduction in maximal respiration (p = 0.4035, ns) and demonstrated a 70% loss of spare respiratory capacity (p = 0.4143, ns) with significantly impaired adaptation to BSO challenge (long COVID + BSO: 9.9 vs. control + BSO: 54 pmol/min, p = 0.0091). Proton leak, a protective mechanism against ROS overproduction, was blunted in long COVID monocytes (3-fold vs. 13-fold elevation in controls, p = 0.0294). Paradoxically, long COVID monocytes showed reduced ROS accumulation after BSO treatment (6% decrease vs. 1.2-fold increase in controls, p = 0.0015) and elevated mitochondrial membrane potential (157 vs. 113.7 TMRE fluorescence, p = 0.0179), which remained stable under oxidative stress. mtDNA analysis revealed severe depletion (80% reduction, p < 0.001) and region-specific damage, with 75% and 70% reductions in amplification efficiency for regions C and D (p < 0.05), respectively. In contrast, exposure of healthy monocytes to SARS-CoV-2 spike protein did not recapitulate these defects, with preserved basal respiration, ATP production, and spare respiratory capacity, though coupling efficiency under oxidative stress was reduced (p < 0.05).

These findings suggest that mitochondrial dysfunction in long COVID syndrome arises from maladaptive host responses rather than direct viral toxicity, characterized by bioenergetic failure, impaired stress adaptation, and mitochondrial genomic instability. This study identifies persistent mitochondrial dysfunction in long COVID monocytes as a critical driver of cardiovascular complications in PASC. Key defects—bioenergetic failure, impaired stress adaptation and mtDNA damage—correlate with clinical symptoms like heart failure and exercise intolerance. The stable elevation of mitochondrial membrane potential and resistance to ROS induction suggest maladaptive remodeling of mitochondrial physiology.

These findings position mitochondrial resilience as a therapeutic target, with potential strategies including antioxidants, mtDNA repair agents or metabolic modulators. The dissociation between spike protein exposure and mitochondrial dysfunction highlights the need to explore host-directed mechanisms in PASC pathophysiology. This work advances our understanding of long COVID cardiovascular sequelae and provides a foundation for biomarker development and targeted interventions to mitigate long-term morbidity.

Link | PDF (International Journal of Molecular Sciences) [Open Access]

 

[wigglethemouse]

Some blood was obtained from a blood bank. I wish all the blood samples had been collected and processed the same way so there would be more confidence in the data.

Institutional Review Board Statement
Human blood leukocyte reduction filters from healthy subjects were received from the blood bank of the University Hospital Münster. The study was conducted according to the principles of the Declaration of Helsinki. Written informed consent was obtained from all donors by the blood bank, and leukocyte reduction filters were provided anonymously without sharing personal and detailed information. This study was approved by the local ethics committee of Münster University Hospital, Germany. All the long COVID patients and healthy individuals provided written informed consent to participate in the study. The ethical permission number is 2019-011-f-S and was approved on 11th March 2019. The study conforms to the Declaration of Helsinki.

I don't actually understand what the blood bank samples were used for if they were "anonymously without sharing personal and detailed information" as they had the data for healthy controls???? What are "reduction filters"?

 

[SNT Gatchaman]

I don't actually understand what the blood bank samples were used for if they were "anonymously without sharing personal and detailed information" as they had the data for healthy controls????

The main study was looking at bioenergetics between the monocyte subset from LC and well-matched healthy controls.

The patients were matched with unaffected controls for age, sex, and cardiovascular risk factors (history of smoking, diabetes mellitus, dyslipidemia, hypertension, and family history of cardiovascular diseases).

They wanted to know if viral proteins (specifically spike S1) caused the same changes. Perhaps they had insufficient samples from the original 10 HCs for this part of the study.

Similar to our findings in long COVID patient monocytes, we hypothesized that direct exposure to SARS-CoV-2 components might impair mitochondrial function in healthy monocytes. Since mitochondrial dysfunction appears to be a hallmark of long COVID syndrome, we investigated whether the viral spike protein alone could recapitulate these effects in vitro. We tested this by exposing CD14++ monocytes from healthy donors to recombinant SARS-CoV-2 spike protein S1 for 20 h, with or without subsequent BSO treatment to induce oxidative stress.

What are "reduction filters"?

Wikipedia states —

Leucocyte depletion, usually by a leucocyte filter included in the blood bag system, is an efficient yet relatively cheap way of reducing the risk of transfusion reactions. Leucocyte depletion is most commonly performed as an integrated processing step, as bedside filtration is considered a less efficient method.

BloodBank Guy writes —

The process of removing white blood cells from a blood product prior to transfusion, primarily by filtration. So-called “leukocyte reduction filters” are part of a whole blood collection bag set, so that after a unit of blood is collected, it can be quickly filtered without breaking the sterility of the product. Modern apheresis equipment has built-in leukocyte reduction capability, as well, so products collected via apheresis are almost always leukoreduced.

There are three well-accepted reasons to leukocyte-reduce blood products:

• Prevention of alloimmunization to foreign HLA antigens
• Prevention of febrile nonhemolytic transfusion reactions
• Prevention of CMV transmission (though this one is admittedly still debated)

Many also believe that leukoreduction helps prevent the immunosuppression that occurs after transfusion (so-called “transfusion-related immunomodulation, or “TRIM”). Leukocyte reduction may also play a role in decreasing bacterial contamination of blood products, and prevention of transmission of prions (such as the vector of variant Creutzfeldt-Jakob disease), though these are less accepted indications.