title: mtDNA germ line variation mediated ROS generates retrograde signaling and induces pro-cancerous metabolic features.
abstract: mtDNA non-synonymous germ line variation (G10398A; p.A114T) has remained equivocal with least mechanistic understanding in showing an association with cancer. This has necessitated showing in-vitro how an over-expression within mitochondria of either of the variants produces higher intracellular ROS, resulting in differential anchorage dependent and independent growth. Both these features were observed to be relatively higher in ND3:114T variant. An elevated amount of intracellular carbonylated proteins and a reduced activity of a key glycolytic enzyme, Pyruvate kinase M2, along with high glucose uptake and lactate production were other pro-cancerous features observed. The retrograde signaling through surplus ROS was generated by post-ND3 over-expression regulated nuclear gene expression epigenetically, involving selectively the apoptotic-DDR-pathways. The feature of ND3 over-expression, inducing ROS mediated pro-cancerous features in the cells in in vitro, was replicated in a pilot study in a limited number of sporadic breast tumors, suggesting the importance of mitochondrial germ-line variant(s) in enabling the cells to acquire pro-cancerous features.
authors.affiliation: National Centre of Applied Human Genetics, School of life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
authors.forename: Rajnish Kumar
authors.initials: RK
authors.lastname: Singh
authors.affiliation: National Centre of Applied Human Genetics, School of life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
authors.forename: Archita
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: School of Biotechnology, Shri Mata Vaishno Devi University, Kakriyal, Katra, Jammu &Kashmir, 182320, India.
authors.forename: Ponnusamy
authors.initials: P
authors.lastname: Kalaiarasan
authors.affiliation: School of Biotechnology, Shri Mata Vaishno Devi University, Kakriyal, Katra, Jammu &Kashmir, 182320, India.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Manvati
authors.affiliation: National Centre of Applied Human Genetics, School of life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
authors.forename: Rupali
authors.initials: R
authors.lastname: Chopra
authors.affiliation: National Centre of Applied Human Genetics, School of life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
authors.forename: Rameshwar N K
authors.initials: RN
authors.lastname: Bamezai
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005854:Germ Cells; D006801:Humans; D018384:Oxidative Stress / Q000235:genetics; D011770:Pyruvate Kinase / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D011770:Pyruvate Kinase