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MLH1 deficiency leads to deregulated mitochondrial metabolism.
Rashid, Sukaina; Freitas, Marta O; Cucchi, Danilo; Bridge, Gemma; Yao, Zhi; Gay, Laura; Williams, Marc; Wang, Jun; Suraweera, Nirosha; Silver, Andrew; McDonald, Stuart A C; Chelala, Claude; Szabadkai, Gyorgy; Martin, Sarah A.
Afiliación
  • Rashid S; Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
  • Freitas MO; Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
  • Cucchi D; Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
  • Bridge G; Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
  • Yao Z; Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, WC1E 6BT, UK.
  • Gay L; Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
  • Williams M; Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
  • Wang J; Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
  • Suraweera N; Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
  • Silver A; Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
  • McDonald SAC; Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
  • Chelala C; Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
  • Szabadkai G; Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, WC1E 6BT, UK.
  • Martin SA; Department of Biomedical Sciences, University of Padua, Padua, 35131, Italy.
Cell Death Dis ; 10(11): 795, 2019 10 22.
Article en En | MEDLINE | ID: mdl-31641109
The DNA mismatch repair (MMR) pathway is responsible for the repair of base-base mismatches and insertion/deletion loops that arise during DNA replication. MMR deficiency is currently estimated to be present in 15-17% of colorectal cancer cases and 30% of endometrial cancers. MLH1 is one of the key proteins involved in the MMR pathway. Inhibition of a number of mitochondrial genes, including POLG and PINK1 can induce synthetic lethality in MLH1-deficient cells. Here we demonstrate for the first time that loss of MLH1 is associated with a deregulated mitochondrial metabolism, with reduced basal oxygen consumption rate and reduced spare respiratory capacity. Furthermore, MLH1-deficient cells display a significant reduction in activity of the respiratory chain Complex I. As a functional consequence of this perturbed mitochondrial metabolism, MLH1-deficient cells have a reduced anti-oxidant response and show increased sensitivity to reactive oxidative species (ROS)-inducing drugs. Taken together, our results provide evidence for an intrinsic mitochondrial dysfunction in MLH1-deficient cells and a requirement for MLH1 in the regulation of mitochondrial function.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Homólogo 1 de la Proteína MutL / Mitocondrias Límite: Female / Humans / Male Idioma: En Revista: Cell Death Dis Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Imprimir
XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Homólogo 1 de la Proteína MutL / Mitocondrias Límite: Female / Humans / Male Idioma: En Revista: Cell Death Dis Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido