Mitochondrial Reactive Oxygen Species: A Unifying Mechanism in Long COVID and Spike Protein-Associated Injury: A Narrative Review.

Post-acute sequelae of SARS-CoV-2 infection (long COVID) present with persistent fatigue, cognitive impairment, and autonomic and multisystem dysfunctions that often go unnoticed by standard diagnostic tests. Increasing evidence suggests that mitochondrial dysfunction and oxidative stress are central drivers of these post-viral sequelae. Viral infections, particularly SARS-CoV-2, disrupt mitochondrial bioenergetics by altering membrane integrity, increasing mitochondrial reactive oxygen species (mtROS), and impairing mitophagy, leading to sustained immune activation and metabolic imbalance. This review synthesizes an understanding of how mitochondrial redox signaling and impaired clearance of damaged mitochondria contribute to chronic inflammation and multisystem organ symptoms in both long COVID and post-vaccine injury. We discuss translational biomarkers and non-invasive techniques, exploring therapeutic strategies that include pharmacological, non-pharmacological, and nutritional approaches, as well as imaging modalities aimed at assessing and restoring mitochondrial health. Recognizing long COVID as a mitochondrial disorder that stems from redox imbalance will open new options for personalized treatment and management guided by biomarkers. Future clinical trials are essential to validate these approaches and translate mitochondrial resuscitation into effective care for patients suffering from long COVID and related post-viral syndromes.