Graphical Abstract

Background and Objectives. The importance of mitochondria in inflammatory pathologies, besides providing energy, is associated with the release of mitochondrial damage products, such as mitochondrial DNA (mt-DNA), which may perpetuate inflammation. In this review, we aimed to show the importance of mitochondria, as organelles that produce energy and intervene in multiple pathologies, focusing mainly in COVID-19 and using multiple molecular mechanisms that allow for the replication and maintenance of the viral genome, leading to the exacerbation and spread of the inflammatory response. The evidence suggests that mitochondria are implicated in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which forms double-membrane vesicles and evades detection by the cell defense system. These mitochondrion-hijacking vesicles damage the integrity of the mitochondrion’s membrane, releasing mt-DNA into circulation and triggering the activation of innate immunity, which may contribute to an exacerbation of the pro-inflammatory state. Conclusions. While mitochondrial dysfunction in COVID-19 continues to be studied, the use of mt-DNA as an indicator of prognosis and severity is a potential area yet to be explored.

IntroductionDuring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the virus hijacks the mitochondria causing damage of its membrane and release of mt-DNA into the circulation which can trigger innate immunity and generate an inflammatory state. In this study, we explored the importance of peripheral blood mt-DNA as an early predictor of evolution in patients with COVID-19 and to evaluate the association between the concentration of mt-DNA and the severity of the disease and the patient’s outcome.MethodsA total 102 patients (51 COVID-19 cases and 51 controls) were included in the study. mt-DNA obtained from peripheral blood was quantified by qRT-PCR using the NADH mitochondrial gene.ResultsThere were differences in peripheral blood mt-DNA between patients with COVID-19 (4.25 ng/μl ± 0.30) and controls (3.3 ng/μl ± 0.16) (p = 0.007). Lower mt-DNA concentrations were observed in patients with severe COVID-19 when compared with mild (p= 0.005) and moderate (p= 0.011) cases of COVID-19. In comparison with patients with severe COVID-19 who survived (3.74 ± 0.26 ng/μl) decreased levels of mt-DNA in patients with severe COVID-19 who died (2.4 ± 0.65 ng/μl) were also observed (p = 0.037).ConclusionHigh levels of mt-DNA were associated with COVID-19 and its decrease could be used as a potential biomarker to establish a prognosis of severity and mortality of patients with COVID-19.

Chronic hyperglycemia increases the risk of developing severe COVID-19 symptoms, but the related mechanisms are unclear. A mean glucose level upon hospital admission >166 mg/dl correlates positively with acute respiratory distress syndrome in patients with hyperglycemia. The objective of this study was to evaluate the relationship between sustained hyperglycemia and the outcome of hospitalized patients with severe COVID-19. We also evaluated the effect of high glucose concentrations on the expression of angiotensin-converting enzyme 2 (ACE2). We carried out a case-control study with hospitalized patients with severe COVID-19 with and without sustained hyperglycemia. In a second stage, we performed in vitro assays evaluating the effects of high glucose concentrations on ACE2 gene expression. Fifty hospitalized patients with severe COVID-19 were included, of which 28 (56%) died and 22 (44%) recovered. Patients who died due to COVID-19 and COVID-19 survivors had a high prevalence of hyperglycemia (96.4% versus 90.9%), with elevated central glucose upon admission (197.7 mg/dl versus 155.9 mg/dl, p = 0.089) and at discharge (185.2 mg/dl versus 134 mg/dl, p = 0.038). The mean hypoxemia level upon hospital admission was 81% in patients who died due to COVID-19 complications and 88% in patients who survived (p = 0.026); at the time of discharge, hypoxemia levels were also different between the groups (68% versus 92%, p ≤ 0.001). In vitro assays showed that the viability of A549 cells decreased (76.41%) as the glucose concentration increased, and the ACE2 gene was overexpressed 9.91-fold after 72 h (p ≤ 0.001). The relationship between hyperglycemia and COVID-19 in hospitalized patients with COVID-19 plays an important role in COVID-19-related complications and the outcome for these patients. In patients with chronic and/or sustained hyperglycemia, the upregulation of ACE2, and its potential glycation and malfunction, could be related to complications observed in patients with COVID-19.

Since the appearance of the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 in China, diabetes mellitus (DM) and hyperglycemia in patients infected with SARS-CoV, represent independent predictors of mortality. Therefore, metabolic control has played a major role in the prognosis of these patients. In the current pandemic of coronavirus disease 19 (COVID-19), multiple studies have shown that DM is one of the main comorbidities associated with COVID-19 and higher risk of complications and death. The incidence and prevalence of COVID-19 complications and death related with hyperglycemia in patients with or without DM are high. There are many hypotheses related with worse prognosis and death related to COVID-19 and/or hyperglycemia. However, the information about the interplay between hyperglycemia and angiotensin-converting enzyme 2 (ACE2), the critical receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in the context of SARS-CoV-2 infection, is almost null, but there is enough information to consider the possible participation of hyperglycemia in the glycation of this protein, unleashing a pool of reactions leading to acute respiratory distress syndrome and death in patients with COVID-19. In this document we investigated the current evidence related with ACE2 as a key element within the pathophysiological mechanism related with hyperglycemia extrapolating it to context of SARS-CoV-2 infection and its relationship with worse prognosis and death for COVID-19.