UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

MLH1 deficiency leads to deregulated mitochondrial metabolism

Rashid, S; Freitas, MO; Cucchi, D; Bridge, G; Yao, Z; Gay, L; Williams, M; ... Martin, SA; + view all (2019) MLH1 deficiency leads to deregulated mitochondrial metabolism. Cell Death & Disease , 10 , Article 795. 10.1038/s41419-019-2018-y. Green open access

[img]
Preview
Text
Szabadkai_MLH1 deficiency leads to deregulated mitochondrial metabolism_VoR.pdf - Published version

Download (1MB) | Preview

Abstract

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.

Type: Article
Title: MLH1 deficiency leads to deregulated mitochondrial metabolism
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41419-019-2018-y
Publisher version: https://doi.org/10.1038/s41419-019-2018-y
Language: English
Additional information: © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
Keywords: Cancer metabolism, Cell biology
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10085104
Downloads since deposit
3Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item