Mitochondrial DNA mutations contribute to high altitude pulmonary edema via increased oxidative stress and metabolic reprogramming during hypobaric hypoxia

Sharma, Swati; Singh, Yamini; Sandhir, Rajat; Singh, Sayar; Ganju, Lilly; Kumar, Bhuvnesh; Varshney, Rajeev K.

doi:10.1016/j.bbabio.2021.148431

Cited by 13 publications

(9 citation statements)

References 53 publications

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“…The study also revealed that haplogroup D might be more susceptible to DNA damage from external ROS caused by cigarette smoking 24 . Our previous studies on Indian male low landers showed the association of haplogroups M33a2′3 and H2a2a1 with increased susceptibility of High‐Altitude Pulmonary Edema 25,26 . A mitochondrial haplogroup study of 782 individuals of Han chinese population showed that haplogroup D is associated with the pathogenesis of end stage renal disease altering the mtDNA copy number 27 .…”

Section: Discussionmentioning

confidence: 88%

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

Kumari

Singh

et al. 2023

Journal of Medical Virology

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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.

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Section: Discussionmentioning

confidence: 88%

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

Kumari

Singh

et al. 2023

Journal of Medical Virology

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“…Similar to that of HACE, the pathogenesis of HAPE in rats exposed to acute hypobaric hypoxia (7620 m; 24 h) involves increased ROS levels, trending toward levels causing oxidative stress and contributing to an increase in transvascular leakage; the same study showed that the expression of NF-κB, pro-inflammatory cytokines (IL-1, IL-6, and TNFα), and adhesion molecules (VCAM-1, ICAM1, P-selectin, and E-selectin) is increased, indicating that increases in ROS (H 2 O 2 ), MDA, and pro-inflammatory molecule levels drive positive regulatory feedback [ 10 ]. Additionally, a recent study on HAPE induced by acute hypobaric hypoxia exposure (3250 m; 7 days) suggested that mutations in mitochondrial DNA complex I subunits may cause mitochondrial respiratory chain dysfunction, leading to oxidative stress, as determined by an increase in lipid peroxidation and protein carbonylation [ 58 ].…”

Section: Oxidative Stress and High-altitude Diseasesmentioning

confidence: 99%

“…In addition, increased oxidative stress in HAPE patients compared to that in acclimatized controls may have been due to decreased SOD activity [ 58 ], although Sarada et al [ 10 ] showed that after 6 h of exposure, the level of antioxidant enzymes, such as SOD, was increased in HAPE patients. This difference may be attributable to the duration of exposure to acute hypobaric hypoxia and the models used in the two studies mentioned in the paragraph above.…”

Section: Oxidative Stress and High-altitude Diseasesmentioning

confidence: 99%

Oxidative Stress and Diseases Associated with High-Altitude Exposure

2022

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Several diseases associated with high-altitude exposure affect unacclimated individuals. These diseases include acute mountain sickness (AMS), high-altitude cerebral edema (HACE), high-altitude pulmonary edema (HAPE), chronic mountain sickness (CMS), and, notably, high-altitude pulmonary hypertension (HAPH), which can eventually lead to right ventricle hypertrophy and heart failure. The development of these pathologies involves different molecules and molecular pathways that might be related to oxidative stress. Studies have shown that acute, intermittent, and chronic exposure to hypobaric hypoxia induce oxidative stress, causing alterations to molecular pathways and cellular components (lipids, proteins, and DNA). Therefore, the aim of this review is to discuss the oxidative molecules and pathways involved in the development of high-altitude diseases. In summary, all high-altitude pathologies are related to oxidative stress, as indicated by increases in the malondialdehyde (MDA) biomarker and decreases in superoxide dismutase (SOD) and glutathione peroxidase (GPx) antioxidant activity. In addition, in CMS, the levels of 8-iso-PGF2α and H2O2 are increased, and evidence strongly indicates an increase in Nox4 activity in HAPH. Therefore, antioxidant treatments seem to be a promising approach to mitigating high-altitude pathologies.

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“…Similarly, hypoxia inhibits the transcription of mitochondrial DNA and damages the structure and function of mitochondria. Consequently, mitochondrial protein-coding genes are expected to experience selective pressures in species that are continuously exposed to harsh environmental conditions [ 2 , 25 , 26 ]…”

Section: Introductionmentioning

confidence: 99%

The mitochondrial genome of the mountain wooly tapir, Tapirus pinchaque and a formal test of the effect of altitude on the adaptive evolution of mitochondrial protein coding genes in odd-toed ungulates

Gutiérrez,

Ortega,

Savoie

et al. 2023

BMC Genomics

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Background The harsh conditions of high-altitude environments are known to drive the evolution of physiological and morphological traits in endothermic animals. These conditions are expected to result in the adaptive evolution of protein coding genes encoded in mitochondrial genomes that are vital for the oxidative phosphorylation pathway. In this study, we formally tested for signatures of adaptive evolution on mitochondrial protein coding genes in Tapirus pinchaque and other odd-toed ungulates inhabiting high-elevation environments. Results The AT-rich mitochondrial genome of T. pinchaque is 16,750 bp long. A phylomitogenomic analysis supports the monophyly of the genus Tapirus and families in the Perissodactyla. The ratio of non-synonymous to synonymous substitutions demonstrated that all mitochondrial genes undergo purifying selection in T. pinchaque and other odd ungulates living at high elevations. Over this negative background selection, Branch Models suggested that cox3 and nad6 might be undergoing stronger purifying selection than other mitochondrial protein coding genes. Furthermore, Site Models suggested that one and four sites in nad2 and nad5, respectively, could be experiencing positive selection. However, these results were supported by Likelihood Ratio Tests but not Bayesian Empirical Bayes posterior probabilities. Additional analyses (in DataMonkey) indicated a relaxation of selection strength in nad6, evidence of episodic diversifying selection in cob, and revealed episodic positive/diversifying selection signatures for two sites in nad1, and one site each in nad2 and nad4. Conclusion The mitochondrial genome of T. pinchaque is an important genomic resource for conservation of this species and this study contributes to the understanding of adaptive evolution of mitochondrial protein coding genes in odd-toed ungulates inhabiting high-altitude environments.

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Mitochondrial DNA mutations contribute to high altitude pulmonary edema via increased oxidative stress and metabolic reprogramming during hypobaric hypoxia

Cited by 13 publications

References 53 publications

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

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

Oxidative Stress and Diseases Associated with High-Altitude Exposure

The mitochondrial genome of the mountain wooly tapir, Tapirus pinchaque and a formal test of the effect of altitude on the adaptive evolution of mitochondrial protein coding genes in odd-toed ungulates

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