MLH1 deficiency leads to deregulated mitochondrial metabolism
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Sukaina Rashid Marta O Freitas Danilo Cucchi Gemma Bridge Zhi Yao Laura Gay Marc Williams Jun Wang Nirosha Suraweera Andrew Silver Stuart AC McDonald Claude Chelala Gyorgy Szabadkai Sarah A MartinAbstract
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.
Journal details
Journal Cell Death and Disease
Volume 10
Issue number 11
Pages 795
Available online
Publication date
Full text links
Publisher website (DOI) 10.1038/s41419-019-2018-y
Europe PubMed Central 31641109
Pubmed 31641109
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