Mitochondrial Dysfunction and the Immuno-inflammatory Response Induced by SARS-CoV-2 Infection: the Role of Mitochondrial DNA

In 2019, a new coronavirus (SARS-CoV-2) was identified in China and had rapidly spread across the world. Its associated disease, coronavirus disease 2019 (COVID-19), has led to millions of deaths in 2020-2021. Studies have been demonstrating that SARS-CoV-2 induces a systemic hyperinflammatory state, which is associated with a decreased cytotoxic capacity and impaired Type I interferon (IFN) response. Moreover, iron dysfunction/hyperferritinemia in association with hyperinflammation leads to oxidative stress and apoptosis. Altogether, these cellular events contribute to COVID-19 severity. In viral infections, systemic and cellular alterations can promote mitochondrial dysfunction. In this regard, dysfunctional mitochondria can trigger the immune response, leading to the release of mitochondrial damage-associated molecular patterns, including mitochondrial DNA (mtDNA) and reactive oxygen species (mtROS). mtDNA is known to promote a beneficial antiviral response; however, sustained nocive stimuli, such as SARS-CoV-2, could turn this response into oxidative stress and exacerbated inflammation leading to tissue injury. In addition, mtDNA can be released into the extracellular space and induce a proinflammatory state in neighboring cells. Here, we highlight the potential role of mtDNA as an important marker of hyperinflammation in the progress of COVID-19. Furthermore, we briefly discuss the role of mtROS and its interactions with the mitochondrial antiviral signaling (MAVS), which can also contribute to COVID-19 immunopathogenesis.