Abstract: The current understanding of long COVID (LC) is still limited. This review highlights key
findings regarding the role of gut microbiota, mitochondria, and the main pathophysiological aspects
of LC revealed by clinical studies, related to the complex interplay between infection, intestinal
dysbiosis, dysfunctional mitochondria, and systemic inflammation generated in a vicious circle,
reflecting the molecular and cellular processes from the “leaky gut” to the “leaky electron transport
chain (ETC)” into a quantum leap. The heterogeneity of LC has hindered progress in deciphering all
the pathophysiological mechanisms, and therefore, the approach must be multidisciplinary, with a
special focus not only on symptomatic management but also on addressing the underlying health
problems of the patients. It is imperative to further assess and validate the effects of COVID-19 and
LC on the gut microbiome and their relationship to infections with other viral agents or pathogens.
Further studies are needed to better understand LC and expand the interdisciplinary points of
view that are required to accurately diagnose and effectively treat this heterogeneous condition.
Given the ability of SARS-CoV-2 to induce autoimmunity in susceptible patients, they should be
monitored for symptoms of autoimmune disease after contracting the viral infection. One question
remains open, namely, whether the various vaccines developed to end the pandemic will also induce
autoimmunity. Recent data highlighted in this review have revealed that the persistence of SARS-
CoV-2 and dysfunctional mitochondria in organs such as the heart and, to a lesser extent, the kidneys,
liver, and lymph nodes, long after the organism has been able to clear the virus from the lungs, could
be an explanation for LC.