Multi-omics analysis of long COVID (post-COVID-19 condition) reveals persistent mitochondrial dysfunction, suppressed oxidative phosphorylation, and immune dysregulation.

Overview

1. Guarnieri Research Group LLC, Philadelphia, PA, United States
2. Ohio University, Heritage College of Osteopathic Medicine, Athens, OH, United States
3. Drexel University College of Medicine, Philadelphia, PA, United States
4. University of Cambridge, Department of Medical Genetics, Cambridge, United Kingdom
5. North Carolina State University, Department of Molecular and Structural Biochemistry, Raleigh, NC, United States
6. Aslinger Scientific Consulting, Round Rock, TX, United States
7. Blue Marble Space Institute of Science, Seattle, WA, United States

Abstract

Introduction: Post-COVID Syndrome (PCS), or long-COVID, is a major public health burden, but its underlying mechanisms remain poorly understood. Because acute SARS-CoV-2 infection induces marked suppression of mitochondrial oxidative phosphorylation (OXPHOS), we investigated whether persistent immunometabolic remodeling is a recurring transcriptional, metabolic, and proteomic feature of PCS.

Methods: We performed an integrated multi-omics analysis of transcriptomic, proteomic, and metabolomic datasets across multiple tissues from Syrian hamster models and human cohorts spanning acute infection through post-acute and PCS stages extending up to 12 months post-infection.

Results: Across species and tissues, we observed overlapping signatures of mitochondrial dysfunction, including sustained suppression of OXPHOS, activation of mitochondrial stress responses, and enrichment of inflammatory pathways. Skeletal muscle exhibited the most pronounced and persistent mitochondrial repression in both hamsters and PCS patient biopsies, consistent with fatigue-associated phenotypes. Hamster heart and kidney tissues also showed persistent OXPHOS suppression, while lung tissue demonstrated prolonged inflammatory signaling despite partial metabolic recovery. In the nervous system, transcriptional profiles revealed region-specific patterns, including persistent cortical mitochondrial repression and partial recovery in sensory-associated regions. Peripheral blood mononuclear cells (PBMCs) transcriptomics and serum metabolic datasets suggested prolonged downregulation of OXPHOS-associated programs up to 12 months post-infection, potentially contributing to persistent immune dysregulation in susceptible individuals with underlying conditions. Longitudinal serum proteomics in PCS patients revealed sustained mitochondrial stress responses, increased oxidative stress signatures, and persistent immune activation at 1 and 6 months post-infection compared to recovered controls.

Discussion: Together, these multi-omics results identify persistent mitochondrial repression and immune dysregulation as recurring features across PCS-associated datasets, providing a framework linking bioenergetic dysfunction with chronic immune activation and supporting future mechanistic and therapeutic investigation.

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Data

Datasets cited

• data.mendeley.com/datasets/gc9g2g53kr, at Mendeley Data; found in the text, “Overview”
• geo:GSE231910, at NCBI GEO; found in the text, “Overview”

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Reproduced under the paper's license (CC BY), from the paper cited above.

Materials availability

This study did not generate new, unique reagents or materials. All datasets analyzed in this research were obtained from publicly accessible datasets. The specific references and dataset accession numbers are listed in the “Experimental Model and Subject Details” below. Custom pathways used for gene set analysis are described in detail in “Methods Details” below.

Reproduced under the paper's license (CC BY), from the paper cited above.

Data Availability Statement

All data used in this study are publicly available and can be accessed through their respective repository using the accession numbers listed in the “Experimental Model and Subject Details” section below. Code and gene lists utilized in this paper, can be found at https://github.com/easlinger, and https://github.com/shehbeel. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, volume, pages, dates, 6 authors, 7 keywords, 14 MeSH terms, 66 references.

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This paper

Tasoula, A., Arif, S., Waisberg, E., Bauer, L., Aslinger, E., & Guarnieri, J. W. (2026). Multi-omics analysis of long COVID (post-COVID-19 condition) reveals persistent mitochondrial dysfunction, suppressed oxidative phosphorylation, and immune dysregulation. Frontiers in immunology, 17, 1776555. https://doi.org/10.3389/fimmu.2026.1776555

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