AAV-mediated transduction of the nuclear-coded mitochondrial Ant1 gene ameliorates cardiomyopathy in Ant1-/- mouse: A step toward treating mitochondrial disease.
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ABSTRACT:
PROVIDER: PRJNA1181802 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR31219200.fastq.gz | Fastqsanger.gz | |||
| SRR31219201.fastq.gz | Fastqsanger.gz | |||
| SRR31219202.fastq.gz | Fastqsanger.gz | |||
| SRR31219203.fastq.gz | Fastqsanger.gz |
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Project description:Macrophage-mediated inflammation drives various lung diseases, including chronic obstructive pulmonary disease (COPD). COPD macrophages have dysfunctional mitochondrial metabolism and function which lead to a chronic inflammatory lung environment. However, the factors regulating this altered metabolism have not been elucidated. Adenine nucleotide translocase 1 (ANT1) is a mitochondrial ATP transporter critical to mitochondrial metabolism. We demonstrate that human alveolar macrophages from patients with moderate COPD (GOLD stage 2) have reduced ANT1 expression while macrophages from very severe COPD (GOLD stage 4) has elevated ANT1 compared to normal control subjects. Ant1-deficient mice were protected against cigarette smoke (CS)-induced emphysema with failure of recruited immune cells to migrate into alveoli. Ant1-null alveolar macrophages had reduced ATP production and mitochondrial respiration, upregulated fewer inflammatory pathways after CS and reduced migratory capacity. Conditional Ant1 knockout in Cx3cr1-positive monocytes and adoptive transfer of Ant1-deficient bone marrow into CS-treated mice phenocopied the migratory defect in the lung. Our data indicate that ANT1 is a critical regulator of lung macrophage inflammatory signaling and CS-triggered cell migration in the lung, suggesting that metabolic modulation may be a promising therapeutic avenue for COPD
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