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Title: Identification of a novel mitochondria-localized LKB1 variant required for the regulation of the oxidative stress response
Authors: Tan, Ivan
Xu, Shengli
Huo, Jianxin
Huang, Yuhan
Lim, Hong-Hwa
Lam, Kong-Peng
Keywords: Science::Biological sciences
Issue Date: 2023
Source: Tan, I., Xu, S., Huo, J., Huang, Y., Lim, H. & Lam, K. (2023). Identification of a novel mitochondria-localized LKB1 variant required for the regulation of the oxidative stress response. Journal of Biological Chemistry, 299(7), 104906-.
Journal: Journal of Biological Chemistry 
Abstract: The tumor suppressor Liver Kinase B1 (LKB1) is a multifunctional serine/threonine protein kinase that regulates cell metabolism, polarity, and growth and is associated with Peutz-Jeghers Syndrome and cancer predisposition. The LKB1 gene comprises 10 exons and 9 introns. Three spliced LKB1 variants have been documented, and they reside mainly in the cytoplasm, although two possess a nuclear-localization sequence (NLS) and are able to shuttle into the nucleus. Here, we report the identification of a fourth and novel LKB1 isoform that is, interestingly, targeted to the mitochondria. We show that this mitochondria-localized LKB1 (mLKB1) is generated from alternative splicing in the 5' region of the transcript and translated from an alternative initiation codon encoded by a previously unknown exon 1b (131 bp) hidden within the long intron 1 of LKB1 gene. We found by replacing the N-terminal NLS of the canonical LKB1 isoform, the N-terminus of the alternatively spliced mLKB1 variant encodes a mitochondrial transit peptide that allows it to localize to the mitochondria. We further demonstrate that mLKB1 colocalizes histologically with mitochondria-resident ATP Synthase and NAD-dependent deacetylase sirtuin-3, mitochondrial (SIRT3) and that its expression is rapidly and transiently upregulated by oxidative stress. We conclude that this novel LKB1 isoform, mLKB1, plays a critical role in regulating mitochondrial metabolic activity and oxidative stress response.
ISSN: 0021-9258
DOI: 10.1016/j.jbc.2023.104906
Schools: School of Biological Sciences 
Organisations: Singapore Immunology Network, A*STAR 
Yong Loo Lin School of Medicine, NUS 
Rights: © 2023 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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