Prognostic value of circulating mitochondrial DNA in prostate cancer and underlying mechanism

• Published in: Mitochondrion Vol. 71; pp. 40 - 49
• Main Authors: Borah, Supriya, Mishra, Rajeev, Dey, Sananda, Suchanti, Surabhi, Bhowmick, Neil A., Giri, Biplab, Haldar, Subhash
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-07-2023
• Subjects: Biomarker; Cell-free DNA; Mitochondrial DNA; mtDNA; Prostate cancer; Tumor microenvironment; Cell-free DNA; Biomarker; Mitochondrial DNA; Tumor microenvironment; mtDNA; Prostate cancer
• ISSN: 1567-7249; 1872-8278
• DOI: 10.1016/j.mito.2023.05.005

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•Prostate tumor microenvironment, mtDNA/complement C3a positive feedback paracrine loop is actively involved in cancer-associated stromal fibroblastic co-evolution and subsequent cancer progression.•cmtDNA copy number and mutations in its genes might be considered potential prognostic biomarkers to understand the stages of cancer progression, cancer diagnosis, and treatment outcome.•Increase in cmtDNA copy number, decrease in cmtDNA size, and mutations of different mtDNA genes specifically MT-ND2, MT-ATP8, and MT-ATP6 (m.8993 T > G & m.8932C > T) are correlated with severity and progression of prostate cancer.•Such mtDNA characteristics may enhance the diagnostic and prognostic value when measured along with PSA level to determine prostate cancer stages, CRPC metastasis, and treatment outcome in comparison to PSA alone.
Circulating DNAs are considered as degraded DNA fragments of approximately 50–200 bp, found in blood plasma, consisting of cell-free mitochondrial and nuclear DNA. Such cell-free DNAs in the blood are found to be altered in different pathological conditions including lupus, heart disease, and malignancies. While nuclear DNAs are being used and being developed as a powerful clinical biomarker in liquid biopsies, mitochondrial DNAs (mtDNAs) are associated with inflammatory conditions including cancer progression. Patients with cancer including prostate cancer are found to have measurable concentrations of mitochondrial DNA in circulation in comparison with healthy controls. The plasma content of mitochondrial DNA is dramatically elevated in both prostate cancer patients and mouse models treated with the chemotherapeutic drug. Cell-free mtDNA, in its oxidized form, induced a pro-inflammatory condition and activates NLRP3-mediated inflammasome formation which causes IL-1β-mediated activation of growth factors. On the other hand, interacting with TLR9, mtDNAs trigger NF-κB-mediated complement C3a positive feedback paracrine loop and activate pro-proliferating signaling through upregulating AKT, ERK, and Bcl2 in the prostate tumor microenvironment. In this review, we discuss the growing evidence supporting cell-free mitochondrial DNA copy number, size, and mutations in mtDNA genes as potential prognostic biomarkers in different cancers and targetable prostate cancer therapeutic candidates impacting stromal-epithelial interactions essential for chemotherapy response.