Blood mitochondrial DNA as a biomarker of clinical outcomes in idiopathic pulmonary fibrosis

Yoon, Hee‐Young; Choi, Kwang Hun; Kim, Min Ji; Kim, Haksu; Song, Jin Woo

doi:10.1183/13993003.01769-2020

Cited by 4 publications

(5 citation statements)

References 13 publications

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“…In accordance with this, mtDNA levels are elevated in both serum (3)(4)(5)(6) and bronchoalveolar lavage uid (BALF) (3,4) in IPF patients. While serum mtDNA levels are associated with survival time (3), disease severity or progression (4,5), and the occurrence of AE (6), the clinical signi cance of mtDNA in BALF (BALF-mtDNA) has not been well studied.…”

Section: Introductionsupporting

confidence: 61%

“…In the eld of IPF, several studies have evaluated the prognostic impact of plasma/serum-mtDNA. Extracellular mtDNA was elevated in plasma or serum from IPF patients, and was associated with shorter survival (3), disease progression (3,5), future development of AE-IPF (6), and clinical parameters representing disease severity, such as lower D L CO and shorter 6-minute walk distance (4). On the other hand, Bruno et al…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a cohort study

Fukihara,

Sakamoto,

Ikeyama

et al. 2024

Preprint

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Background Extracellular mitochondrial DNA (mtDNA) is released from damaged cells and increases in the serum and bronchoalveolar lavage fluid (BALF) of idiopathic pulmonary fibrosis (IPF) patients. While increased levels of serum mtDNA have been reported to be linked to disease progression and the future development of acute exacerbation (AE) of IPF (AE-IPF), the clinical significance of mtDNA in BALF (BALF-mtDNA) remains unclear. We investigated the relationships between BALF-mtDNA levels and other clinical variables and prognosis in IPF. Methods Extracellular mtDNA levels in BALF samples collected from IPF patients were determined using droplet-digital PCR. Levels of extracellular nucleolar DNA in BALF (BALF-nucDNA) were also determined as a marker for simple cell collapse. Patient characteristics and survival information were retrospectively reviewed. Results mtDNA levels in serum and BALF did not correlate with each other. In 27 patients with paired BALF samples obtained in a stable state and at the time of AE diagnosis, BALF-mtDNA levels were significantly increased at the time of AE. Elevated BALF-mtDNA levels were associated with inflammation or disordered pulmonary function in a stable state (n = 90), while being associated with age and BALF-neutrophils at the time of AE (n = 38). BALF-mtDNA ≥ 4234.3 copies/µL in a stable state (median survival time (MST): 42.4 vs. 79.6 months, p < 0.001) and ≥ 11194.3 copies/µL at the time of AE (MST: 2.6 vs. 20.0 months, p = 0.03) were associated with shorter survival after BALF collection, even after adjusting for other known prognostic factors. On the other hand, BALF-nucDNA showed different trends in correlation with other clinical variables and did not show any significant association with survival time. Conclusions Elevated BALF-mtDNA was associated with a poor prognosis in both IPF and AE-IPF. Of note, at the time of AE, it sharply distinguished survivors from non-survivors. Given the trends shown by analyses for BALF-nucDNA, the elevation of BALF-mtDNA might not simply reflect the impact of cell collapse. Further studies are required to explore the underlying mechanisms and clinical applications of BALF-mtDNA in IPF.

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Section: Introductionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a cohort study

Fukihara,

Sakamoto,

Ikeyama

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…In accordance with this, mtDNA levels are elevated in both serum [3][4][5][6][7] and bronchoalveolar lavage fluid (BALF) [3,4] in IPF patients. While serum mtDNA levels are associated with survival time [3,7], disease severity or progression [4,5,7], and the occurrence of AE [6], the clinical significance of mtDNA in BALF (BALF-mtDNA) has not been well studied.…”

Section: Introductionmentioning

confidence: 82%

“…In the field of IPF, several studies have evaluated the prognostic impact of plasma/serum-mtDNA. Extracellular mtDNA was elevated in plasma or serum from IPF patients, and was associated with shorter survival [3,7], disease progression [3,5,7], future development of AE-IPF [6], and clinical parameters representing disease severity, such as lower D L CO and shorter 6-min walk distance [4,7]. On the other hand, Bruno et al demonstrated elevated BALF-mtDNA in IPF [4], although its clinical significance and prognostic impact have not been studied in detail, and how BALF-mtDNA levels alter depending on the disease status has never been investigated.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a single cohort study

Fukihara,

Sakamoto,

Ikeyama

et al. 2024

Respir Res

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Background Extracellular mitochondrial DNA (mtDNA) is released from damaged cells and increases in the serum and bronchoalveolar lavage fluid (BALF) of idiopathic pulmonary fibrosis (IPF) patients. While increased levels of serum mtDNA have been reported to be linked to disease progression and the future development of acute exacerbation (AE) of IPF (AE-IPF), the clinical significance of mtDNA in BALF (BALF-mtDNA) remains unclear. We investigated the relationships between BALF-mtDNA levels and other clinical variables and prognosis in IPF. Methods Extracellular mtDNA levels in BALF samples collected from IPF patients were determined using droplet-digital PCR. Levels of extracellular nucleolar DNA in BALF (BALF-nucDNA) were also determined as a marker for simple cell collapse. Patient characteristics and survival information were retrospectively reviewed. Results mtDNA levels in serum and BALF did not correlate with each other. In 27 patients with paired BALF samples obtained in a stable state and at the time of AE diagnosis, BALF-mtDNA levels were significantly increased at the time of AE. Elevated BALF-mtDNA levels were associated with inflammation or disordered pulmonary function in a stable state (n = 90), while being associated with age and BALF-neutrophils at the time of AE (n = 38). BALF-mtDNA ≥ 4234.3 copies/µL in a stable state (median survival time (MST): 42.4 vs. 79.6 months, p < 0.001) and ≥ 11,194.3 copies/µL at the time of AE (MST: 2.6 vs. 20.0 months, p = 0.03) were associated with shorter survival after BALF collection, even after adjusting for other known prognostic factors. On the other hand, BALF-nucDNA showed different trends in correlation with other clinical variables and did not show any significant association with survival time. Conclusions Elevated BALF-mtDNA was associated with a poor prognosis in both IPF and AE-IPF. Of note, at the time of AE, it sharply distinguished survivors from non-survivors. Given the trends shown by analyses for BALF-nucDNA, the elevation of BALF-mtDNA might not simply reflect the impact of cell collapse. Further studies are required to explore the underlying mechanisms and clinical applications of BALF-mtDNA in IPF.

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“…Malfunctioning mitochondria have frequently been observed in AECII in the lungs of patients with idiopathic pulmonary fibrosis and mice with BLM-induced pulmonary fibrosis [22,23]. Concurrently, serum mtDNA levels in patients with idiopathic pulmonary fibrosis are positively correlated with disease severity [24].…”

Section: Introductionmentioning

confidence: 99%

Abnormal mitochondrial iron metabolism damages alveolar type II epithelial cells involved in bleomycin-induced pulmonary fibrosis

Shao,

Cheng,

et al. 2024

Theranostics

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Rationale: Pulmonary fibrosis is a chronic progressive lung disease with limited therapeutic options. We previously revealed that there is iron deposition in alveolar epithelial type II cell (AECII) in pulmonary fibrosis, which can be prevented by the iron chelator deferoxamine. However, iron in the cytoplasm and the mitochondria has two relatively independent roles and regulatory systems. In this study, we aimed to investigate the role of mitochondrial iron deposition in AECII injury and pulmonary fibrosis, and to find potential therapeutic strategies. Methods: BLM-treated mice, MLE-12 cells, and primary AECII were employed to establish the mouse pulmonary fibrosis model and epithelial cells injury model, respectively. Mitochondrial transplantation, siRNA and plasmid transfection, western blotting (WB), quantitative real-time polymerase chain reaction (RT-qPCR), polymerase chain reaction (PCR), immunofluorescence, immunoprecipitation (IP), MitoSOX staining, JC-1 staining, oxygen consumption rate (OCR) measurement, and Cell Counting Kit-8 (CCK8) assay were utilized to elucidate the role of mitochondrial iron deposition in cell and lung fibrosis and determine its mechanism. Results: This study showed that prominent mitochondrial iron deposition occurs within AECII in bleomycin (BLM)-induced pulmonary fibrosis mouse model and in BLM-treated MLE-12 epithelial cells. Further, the study revealed that healthy mitochondria rescue BLM-damaged AECII mitochondrial iron deposition and cell damage loss. Mitoferrin-2 (MFRN2) is the main transporter that regulates mitochondrial iron metabolism by transferring cytosolic iron into mitochondria, which is upregulated in BLM-treated MLE-12 epithelial cells. Direct overexpression of MFRN2 causes mitochondrial iron deposition and cell damage. In this study, decreased ubiquitination of the ubiquitin ligase F-box/LRR-repeat protein 5 (FBXL5) degraded iron-reactive element-binding protein 2 (IREB2) and promoted MFRN2 expression as well as mitochondrial iron deposition in damaged AECII. Activation of the prostaglandin E2 receptor EP4 subtype (EP4) receptor signaling pathway counteracted mitochondrial iron deposition by downregulating IREB2-MFRN2 signaling through upregulation of FBXL5. This intervention not only reduced mitochondrial iron content but also preserved mitochondrial function and protected against AECII damage after BLM treatment. Conclusion: Our findings highlight the unexplored roles, mechanisms, and regulatory approaches of abnormal mitochondrial iron metabolism of AECII in pulmonary fibrosis. Therefore, this study deepens the understanding of the mechanisms underlying pulmonary fibrosis and offers a promising strategy for developing effective therapeutic interventions using the EP4 receptor activator.

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Blood mitochondrial DNA as a biomarker of clinical outcomes in idiopathic pulmonary fibrosis

Cited by 4 publications

References 13 publications

Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a cohort study

Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a cohort study

Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a single cohort study

Abnormal mitochondrial iron metabolism damages alveolar type II epithelial cells involved in bleomycin-induced pulmonary fibrosis

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