title: Complex-I Alteration and Enhanced Mitochondrial Fusion Are Associated With Prostate Cancer Progression.
abstract: Mitochondria (mt) encoded respiratory complex-I (RCI) mutations and their pathogenicity remain largely unknown in prostate cancer (PCa). Little is known about the role of mtDNA loss on mt integrity in PCa. We determined mtDNA mutation in human and mice PCa and assessed the impact of mtDNA depletion on mt integrity. We also examined whether the circulating exosomes from PCa patients are transported to mt and carry mtDNA or mt proteins. We have employed next generation sequencing of the whole mt genome in human and Hi-myc PCa. The impact of mtDNA depletion on mt integrity, presence of mtDNA, and protein in sera exosomes was determined. A co-culture of human PCa cells and the circulating exosomes followed by confocal imaging determined co-localization of exosomes and mt. We observed frequent RCI mutations in human and Hi-myc PCa which disrupted corresponding complex protein expression. Depletion of mtDNA in PCa cells influenced mt integrity, increased expression of MFN1, MFN2, PINK1, and decreased expression of MT-TFA. Increased mt fusion and expression of PINK1 and DNM1L were also evident in the Hi-myc tumors. RCI-mtDNA, MFN2, and IMMT proteins were detected in the circulating exosomes of men with benign prostate hyperplasia (BPH) and progressive PCa. Circulating exosomes and mt co-localized in PCa cells. Our study identified new pathogenic RCI mutations in PCa and defined the impact of mtDNA loss on mt integrity. Presence of mtDNA and mt proteins in the circulating exosomes implicated their usefulness for biomarker development.
authors.affiliation: Department of Medicine, The University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Julie V
authors.initials: JV
authors.lastname: Philley
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Anbarasu
authors.initials: A
authors.lastname: Kannan
authors.affiliation: Department of Surgery, The University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Qin
authors.affiliation: Department of Surgery, The University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sauter
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Ikebe
authors.affiliation: Department of Biology, The University of Texas at Tyler, Tyler, Texas.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Hertweck
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Troyer
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Semmes
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas.
authors.forename: Santanu
authors.initials: S
authors.lastname: Dasgupta
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004272:DNA, Mitochondrial / Q000097:blood / Q000235:genetics; D018450:Disease Progression; D042967:Electron Transport Complex I / Q000097:blood / Q000235:genetics*; D055354:Exosomes / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D063154:Mitochondrial Dynamics; D009154:Mutation; D010641:Phenotype; D011470:Prostatic Hyperplasia / Q000097:blood / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor; D004272:DNA, Mitochondrial; D042967:Electron Transport Complex I