Mitochondrial COX3 and tRNA Gene Variants Associated with Risk and Prognosis of Idiopathic Pulmonary Fibrosis

• Published in: International journal of molecular sciences Vol. 26; no. 3; p. 1378
• Main Authors: Lee, Li-Na, Jan, I-Shiow, Chou, Wen-Ru, Liu, Wei-Lun, Kuo, Yen-Liang, Chang, Chih-Yueh, Chang, Hsiu-Ching, Liu, Jia-Luen, Hsu, Chia-Lin, Lin, Chia-Nan, Chao, Ke-Yun, Tseng, Chi-Wei, Lee, I-Hsien, Wang, Jann-Tay, Wang, Jann-Yuan
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.02.2025; MDPI
• Subjects: Aged; Aged, 80 and over; Apoptosis; Case-Control Studies; Disease; DNA, Mitochondrial - genetics; Electron Transport Complex IV - genetics; Enzymes; Female; Fibroblasts; Genes; Genetic aspects; Genetic Predisposition to Disease; Genomes; Genomics; Growth factors; Humans; Idiopathic Pulmonary Fibrosis - genetics; Idiopathic Pulmonary Fibrosis - mortality; Idiopathic Pulmonary Fibrosis - pathology; Leukocytes - metabolism; Male; Medical prognosis; Middle Aged; Mitochondria; Mitochondria - genetics; Mitochondrial DNA; Mortality; Newfoundland and Labrador; Patients; Prognosis; Proteins; Pulmonary fibrosis; Risk Factors; RNA, Transfer - genetics; Survival analysis; Taiwan; Transfer RNA; Taiwan; Newfoundland and Labrador; nonsynonymous variant; cytochrome c oxidase subunit 3 (COX3); idiopathic pulmonary fibrosis (IPF); tRNA variant; mitochondrial DNA (mtDNA)
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms26031378

Idiopathic pulmonary fibrosis (IPF) has been associated with mitochondrial dysfunction. We investigated whether mitochondrial DNA variants in peripheral blood leukocytes (PBLs), which affect proteins of the respiratory chain and mitochondrial function, could be associated with an increased risk and poor prognosis of IPF. From 2020 to 2022, we recruited 36 patients (age: 75.3 ± 8.5; female: 19%) with IPF, and 80 control subjects (age: 72.3 ± 9.0; female: 27%). The mitochondrial genome of peripheral blood leukocytes was determined using next-generation sequencing. During a 45-month follow-up, 10 (28%) patients with IPF remained stable and the other 26 (72%) progressed, with 12 (33%) mortalities. IPF patients had more non-synonymous (NS) variants (substitution/deletion/insertion) in mitochondrial COX3 gene (coding for subunit 3 of complex IV of the respiratory chain), and more mitochondrial tRNA variants located in the anticodon (AC) stem, AC loop, variable loop, T-arm, and T-loop of the tRNA clover-leaf structure in PBLs than the control group. The succumbed IPF patients were older, had lower initial diffusion capacity, and higher initial fibrosis score on high-resolution computerized tomography (HRCT) than the alive group. NS variants in mitochondrial COX3 gene and tRNA variants in PBLs were associated with shorter survival. Our study shows that (1) leukocyte mitochondrial COX3 NS variants are associated with risk and prognosis of IPF; (2) leukocyte mitochondrial tRNA variants located in the AC stem, AC loop, variable loop, T-arm, and T-loop of the tRNA clover-leaf structure are associated with risk, and the presence of tRNA variants is associated with poor prognosis of IPF.