Mitochondrial dysfunction in long COVID: mechanisms, consequences, and potential therapeutic approaches

Abstract

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has introduced the medical community to the phenomenon of long COVID, a condition characterized by persistent symptoms following the resolution of the acute phase of infection. Among the myriad of symptoms reported by long COVID sufferers, chronic fatigue, cognitive disturbances, and exercise intolerance are predominant, suggesting systemic alterations beyond the initial viral pathology. Emerging evidence has pointed to mitochondrial dysfunction as a potential underpinning mechanism contributing to the persistence and diversity of long COVID symptoms. This review aims to synthesize current findings related to mitochondrial dysfunction in long COVID, exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances, and endothelial dysfunction. Through a comprehensive analysis of the literature, we highlight the significance of mitochondrial health in the pathophysiology of long COVID, drawing parallels with similar clinical syndromes linked to post-infectious states in other diseases where mitochondrial impairment has been implicated. We discuss potential therapeutic strategies targeting mitochondrial function, including pharmacological interventions, lifestyle modifications, exercise, and dietary approaches, and emphasize the need for further research and collaborative efforts to advance our understanding and management of long COVID. This review underscores the critical role of mitochondrial dysfunction in long COVID and calls for a multidisciplinary approach to address the gaps in our knowledge and treatment options for those affected by this condition.

Keywords: Chronic fatigue; Long COVID; Metabolic disturbances; Mitochondrial dysfunction; Oxidative stress; Post-infectious syndromes; Therapeutic strategies.

Fig. 1

Interplay of mitochondrial dysfunction and long COVID: pathophysiological mechanisms and therapeutic approaches. This figure presents a comprehensive overview of mitochondrial dysfunction in long COVID, illustrating the relationship between mitochondrial impairment and the diverse symptoms of long COVID, as well as potential therapeutic interventions. COVID-19-related mitochondrial dysfunction leads to impaired cellular energy production, increased oxidative stress, and the induction of inflammatory responses. Mitochondrial dysfunction is causally linked to key symptoms associated with long COVID—cognitive disturbances (brain), fatigue and muscle weakness (muscle), breathlessness (lung), and cardiac symptoms (heart)—linked to mitochondrial dysfunction through mechanisms such as energy production deficits, oxidative stress, immune response dysregulation, metabolic disruptions, and vascular and endothelial dysfunction. Therapeutic strategies targeting mitochondrial health, including antioxidants, exercise, dietary modifications, and pharmacological interventions, may mitigate the aforementioned symptoms emphasizing the multifaceted approach required to address long COVID. The importance of further research into mitochondrial function as a potential therapeutic target for long COVID is emphasized, highlighting areas for future investigation such as biomarker identification, longitudinal studies, and the development of novel therapeutics

Fig. 2

Patient selection chart

Fig. 3

Association of serum peroxiredoxin-3 levels between patients with different degrees of fatigue observed in different phases of long COVID syndrome. SF-OSC, severe fatigue in patients with ongoing symptomatic COVID (N = 64); SF-PCS, severe fatigue in patients with post-COVID syndrome (N = 30); NSF-OSC, non-severe fatigue in patients with ongoing symptomatic COVID disease (N = 31); NSF-PCS, non-severe fatigue in patients with post-COVID syndrome (N = 14); OSC, patients who still have symptoms between 4 and 12 weeks after the start of acute symptoms; PCS, people who still have symptoms for more than 12 weeks after the start of acute symptoms. A total binary Chalder Fatigue Scale of 3 or less represents scores of those who have non-severe fatigue (NSF), with scores of 4 or more equating to severe fatigue (SF). Data are presented as individual dots and median with interquartile range. *Significant value (p < 0.05)