title: Mitochondrial functions of RECQL4 are required for the prevention of aerobic glycolysis-dependent cell invasion.
abstract: Germline mutations in RECQL4 helicase are associated with Rothmund-Thomson syndrome, which is characterized by a predisposition to cancer. RECQL4 localizes to the mitochondria, where it acts as an accessory factor during mitochondrial DNA replication. To understand the specific mitochondrial functions of RECQL4, we created isogenic cell lines, in which the mitochondrial localization of the helicase was either retained or abolished. The mitochondrial integrity was affected due to the absence of RECQL4 in mitochondria, leading to a decrease in F1F0-ATP synthase activity. In cells where RECQL4 does not localize to mitochondria, the membrane potential was decreased, whereas ROS levels increased due to the presence of high levels of catalytically inactive SOD2. Inactive SOD2 accumulated owing to diminished SIRT3 activity. Lack of the mitochondrial functions of RECQL4 led to aerobic glycolysis that, in turn, led to an increased invasive capability within these cells. Together, this study demonstrates for the first time that, owing to its mitochondrial functions, the accessory mitochondrial replication helicase RECQL4 prevents the invasive step in the neoplastic transformation process.
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Kumari
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Mansoor
authors.initials: M
authors.lastname: Hussain
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Siddharth
authors.initials: S
authors.lastname: De
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Suruchika
authors.initials: S
authors.lastname: Chandra
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Modi
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Shweta
authors.initials: S
authors.lastname: Tikoo
authors.affiliation: Council for Scientific and Industrial Research - Institute of Genomics and Integrative Biology, Delhi 110007, India.
authors.forename: Archana
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Neuropathology, National Institute of Mental Health & Neurosciences, Bangalore 560029, India.
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Sagar
authors.affiliation: Department of Biochemistry, University of Hyderabad, Gachibowli, Hyderabad 500046, India.
authors.forename: Naresh Babu V
authors.initials: NB
authors.lastname: Sepuri
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India sagar@nii.ac.in.
authors.forename: Sagar
authors.initials: S
authors.lastname: Sengupta
mesh_terms: D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004261:DNA Replication / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D011038:Rothmund-Thomson Syndrome / Q000235:genetics; D056566:Sirtuin 3 / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D004272:DNA, Mitochondrial; D005947:Glucose; D025261:Mitochondrial Proton-Translocating ATPases; D017382:Reactive Oxygen Species; D053484:RecQ Helicases; D056566:Sirtuin 3; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C466093:SIRT3 protein, human; C474451:F1F0-ATP synthase; C506731:RECQL4 protein, human
keywords: Cell invasion; OXPHOS; RECQL4; SIRT3; SOD2