COVID-19 severity is linked to changes in mitochondrial DNA methylation

By Tarun Sai LomteReviewed by Susha Cheriyedath, M.Sc.Jan 20 2026

New evidence from Indian patients shows that severe COVID-19 is associated with distinct mitochondrial methylation signatures and altered mitochondrial proteins, pointing to disrupted energy metabolism as a key feature of critical illness.

Study: SARS-CoV-2 altered mitochondrial DNA methylation in Indian COVID-19 patients. Image Credit: CI Photos / Shutterstock

A recent study published in the journal Scientific Reports found that mitochondrial and nuclear-encoded mitochondrial DNA methylation patterns are altered in patients with coronavirus disease 2019 (COVID-19).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection manifests heterogeneously, ranging from asymptomatic to life-threatening illness. Studies suggest that disease severity is contingent on host factors and have identified genetic polymorphisms associated with immune pathways and host-virus interactions. Exploring genetic and epigenetic risk factors linked to COVID-19 severity and outcomes is paramount to developing effective strategies to mitigate its impact.

Epigenetic modifications are heritable changes in gene expression and play an essential role in gene regulation. DNA methylation, a type of epigenetic modification, has received substantial attention as a biomarker for cancer, thrombosis, and cardiovascular disease. Originally thought to be unmethylated, the mitochondrial genome is reported to contain methylated cytosines. However, the extent, biological relevance, and technical measurement of mitochondrial DNA methylation remain unclear.

Study Design and Methylation Analysis

In the present study, researchers characterized mitochondrial and nuclear-encoded mitochondrial DNA methylation in COVID-19 patients in India. They examined differential methylation of 257 targeted nuclear and mitochondrial genes in 16 COVID-19 patients (including deceased and recovered individuals) and in eight healthy controls (HCs). Participants were recruited between January and April 2022. Over 60% of the sample had comorbidities, predominantly hypertension and type 2 diabetes, which could not be disentangled from COVID-19 effects due to pandemic-related constraints.

Differential methylation analyses were performed using bisulfite sequencing data. The differentially methylated regions (DMRs) were assessed for hypermethylation and hypomethylation. The average percent methylation levels did not differ significantly between COVID-19 patients and HCs. However, over 40% of DMRs were detected in intronic regions, while up to one-third were found in promoter regions. The authors note that bisulfite-based approaches to mitochondrial DNA methylation remain technically challenging and should be interpreted cautiously.

Differential Methylation by Disease Outcome

The deceased group had 728 differentially methylated genes (DMGs), including 364 hypomethylated and 364 hypermethylated genes, compared to HCs. In the recovered group, 188 genes were hypermethylated, and 199 were hypomethylated compared with HCs. Groupwise comparisons were performed to identify DMGs specific to COVID-19 severity, followed by ontological analyses of biological processes, cellular components, and molecular functions.

Furthermore, significant DMGs were subjected to pathway enrichment analyses using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. In the deceased group, 52 hypermethylated and 53 hypomethylated genes were found in promoter regions. In recovered individuals, 19 hypomethylated and 33 hypermethylated genes were found in promoter sites. The deceased group had 69 unique DMGs, compared with 16 in the recovered group.

Oxidative phosphorylation, diabetic cardiomyopathy, metabolic pathways, and thermogenesis were the most enriched pathways associated with hypermethylated genes. Citrate cycle and thermogenesis were enriched for hypomethylated genes.

Mitochondrial Protein Alterations

Finally, to examine the effects of COVID-19 on mitochondrial health, an enzyme-linked immunosorbent assay (ELISA) was performed to assess proteins involved in mitochondrial import and fission in an expanded cohort that included additional COVID-19 patients and controls beyond the methylation analysis.

The concentration of dynamin 1-like (DNM1L), an essential mediator of mitochondrial fission, was higher in COVID-19 patients compared to HCs. In addition, translocase of outer mitochondrial membrane 20 (TOMM20) and TOMM22, which have crucial roles in mitochondrial import and function, were significantly elevated in COVID-19 patients.

Interpretation and Implications

In sum, the findings reveal COVID-19-associated differential methylation patterns affecting mitochondrial and nuclear-encoded mitochondrial genes. DMGs were detected in promoter regions. Gene enrichment analysis revealed terms associated with oxidative phosphorylation, ketone biosynthesis, electron transport chain, ATP metabolic process, tricarboxylic acid cycle, and NADH dehydrogenase complex assembly. Although causality cannot be established and age- and sex-related imbalances may have influenced results, the findings should be considered hypothesis-generating, providing insights into mitochondrial epigenetic regulation and its potential role in COVID-19 pathophysiology.