“Mitochondrial pathogenic mutations and metabolic alterations associated with COVID‐19 disease severity”

Abstract

The severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) caused global pandemic and drastically affected the humankind. Mitochondrial mutations have been found to be associated with several respiratory diseases. Missense mutation and pathogenic mitochondrial variants might unveil the potential involvement of the mitochondrial genome in coronavirus disease 2019 (COVID‐19) pathogenesis. The present study aims to elucidate the role of mitochondrial DNA (mtDNA) mutations, mitochondrial haplogroup, and energy metabolism in disease severity. The study was performed on 58 subjects comprising COVID‐19‐positive (n = 42) and negative (n = 16) individuals. COVID‐19‐positive subjects were further categorized into severe deceased (SD), severe recovered (SR), moderate (Mo), and mild (Mi) patients, while COVID‐19‐negative subjects were healthy control (HC) for the study. High throughput next‐generation sequencing was done to investigate mtDNA mutations and haplogroups. The computational approach was applied to study the effect of mtDNA mutations on protein secondary structure. Real time polymerase chain reaction was used for mtDNA copy number determination and mitochondrial function parameters were also analyzed. We found 15 mtDNA mutations in MT‐ND5, MT‐ND4, MT‐ND2, and MT‐COI genes uniquely associated with COVID‐19 severity affecting the secondary structure of proteins in COVID‐19‐positive subjects. Haplogroup analysis suggests that mtDNA haplogroups M3d1a and W3a1b might be potentially associated with COVID‐19 pathophysiology. The mitochondrial function parameters were significantly altered in severe patients (SD and SR; p < 0.05). No significant relationship was found between mtDNA mutations and oxidative stress markers (p > 0.05). The study highlights the importance of mitochondrial reprogramming in COVID‐19 patients and may provide a feasible approach toward finding a path for therapeutic interventions to COVID‐19 disease.

Association of Inflammatory Mediators with Mitochondrial DNA Variants in Geriatric COVID-19 Patients

“…Specifically, Dirican and colleagues [43] by Sanger sequencing of two specific genes, ATPase6 and Cytb, found that COVID-19 patients displayed more A8860G and G9055A substitutions in the ATPase6 gene and more A15326G, T15454C, and C15452A changes in the Cytb gene. Kumari et al, analyzed whole mtDNA genome by NGS and discovered 15 highly conserved and pathogenic variants associated with COVID-19 in genes of mitochondrial complex I and complex IV [22]. Interestingly, we also found an increase of heteroplasmic variant burden in COVID-19 patients in genes of the same respiratory complexes.…”

“…In addition, the mtDNA analyzed in this study, deriving from middle-old and oldest-old individuals, might have been subjected to repeated events of oxidative stress, resulting in increase of transversions, although this issue has been strongly questioned in recent years, [41,42]. Two previous investigations studied mtDNA variants associated with COVID-19 and they both demonstrated an increment in patient group vs. controls [43,22]. Specifically, Dirican and colleagues [43] by Sanger sequencing of two specific genes, ATPase6 and Cytb, found that COVID-19 patients displayed more A8860G and G9055A substitutions in the ATPase6 gene and more A15326G, T15454C, and C15452A changes in the Cytb gene.…”

“…Peripheral blood cells from patients with COVID-19 showed changes indicative of oxidative stress, such as increase of mitochondrial ROS (mtROS), decrease of superoxide dismutase activity and glutathione, and of αketoglutarate dehydrogenase levels [21,22]. mtROS directly stimulate the production of proinflammatory cytokines [23] which in turn drive oxidative stress and ROS generation, leading to a vicious inflammatory and oxidation cycle in which damaged mitochondria cause further mitochondrial injury [24].…”