Mitochondrial Dysfunction and Telomeric Shortening as Long-term Complications After COVID-19

To evaluate the potential role of telomere shortening and mitochondrial dysfunction in the development of long-term complications of COVID-19, including pulmonary fibrosis.

We analyzed 132 patients from the prospective COVID-FIBROTIC cohort 1 year after hospitalization for bilateral pneumonia. Leukocyte telomere length was measured and compared with that of 78 age- and sex-matched controls. Fibrosis biomarkers and radiological findings were assessed at 2 and 12 months. In a subgroup of 44 patients, mitochondrial protein expression was evaluated 2 years after infection using reverse-phase protein arrays. Associations among telomere length, mitochondrial proteins, inflammatory markers, and fibrotic sequelae were analyzed.

Leukocyte telomere length was significantly shorter in patients than in controls (AUC, 0.84; P<.0001), independent of age or acute disease severity. At 12 months, 29% of patients showed fibrotic lung changes on HRCT. Elevated periostin and IL-6 levels correlated with persistent mitochondrial protein alterations at 2 years. Mitochondrial proteins such as ETFβ and PKM2 differentiated patients with fibrotic sequelae and those with marked telomere attrition, suggesting their role as biomarkers. Moreover, in patients with fibrosis, telomere shortening correlated inversely with ACO1 levels, a protein involved in oxidative stress and iron metabolism.

SARS-CoV-2 infection induces sustained telomere shortening and long-term mitochondrial dysfunction, both of which are associated with fibrotic sequelae. These findings support a pathogenic link among mitochondrial dysregulation, telomere attrition, and pulmonary fibrosis, resembling mechanisms described in idiopathic pulmonary fibrosis. Monitoring these biomarkers may help identify patients at risk of chronic post-COVID complications.