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BMI1 silencing increases mitochondrial damage in Hyperoxia‐induced Acute Lung Injury (HALI) in vivo and invitro models
Author(s) -
HernandezCuervo Helena,
Soundararajan Ramani,
Patil Sahebgowda,
Alleyn Matthew,
Breitzig Mason,
Galam Lakshmi,
Lockey Richard,
Kolliputi Narasaiah
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.05036
Subject(s) - oxidative stress , hyperoxia , mitophagy , reactive oxygen species , mitochondrial ros , in vivo , cancer research , mitochondrion , microbiology and biotechnology , apoptosis , biology , chemistry , lung , medicine , biochemistry , autophagy
Acute Lung Injury (ALI), is a conjunction of signs and symptoms that leads to acute hypoxemic respiratory failure with bilateral pulmonary infiltrates not attributed to cardiogenic origin and decreases in the availability of gas exchange. It is caused by a massive innate immune response, with migration of white blood cells (neutrophils and macrophages principally) and cytokines storm, followed by alterations in mitochondrial function, increase in reactive oxygen species production, and oxidative stress that in turn induces more mitochondrial damage. Several studies have shown that mitochondrial alterations are key events in the mechanism of ALI and reduce mitochondrial dysfunction could be possible target in the treatment of the disease. Some authors have determined that BMI1 has a role in mitochondrial function, but its role is unclear, and the metabolic pathway through which BMI1 regulates mitochondrial function and oxidative stress has not been established. Our study shows that BMI1 plays a pivotal role in mitochondrial function during HALI in vitro and in vivo, and BMI1 silencing or depletion induces mitophagy and reduces cell survival by blocking PI3K pathway mediated by PTEN increases, deteriorates the availability of lung cells to produce ATP and to consume of oxygen recurring to glycolysis. In vivo the depletion of BMI1 decrease the lung compliance and elastance inducing deleterious lung damage in mice, which can lead to worsening of HALI. Our research show BMI1 as a therapeutic target in the treatment of ALI/ARDS.