Mtu1-Mediated Thiouridine Formation of Mitochondrial tRNAs Is Required for Mitochondrial Translation and Is Involved in Reversible Infantile Liver Injury.
Reversible infantile liver failure (RILF) is a unique heritable liver disease characterized by acute liver failure followed by spontaneous recovery at an early stage of life. Genetic mutations in MTU1 have been identified in RILF patients. MTU1 is a mitochondrial enzyme that catalyzes the 2-thiolation of 5-taurinomethyl-2-thiouridine (τm5s2U) found in the anticodon of a subset of mitochondrial tRNAs (mt-tRNAs). Although the genetic basis of RILF is clear, the molecular mechanism that drives the pathogenesis remains elusive. We here generated liver-specific knockout of Mtu1 (Mtu1LKO) mice, which exhibited symptoms of liver injury characterized by hepatic inflammation and elevated levels of plasma lactate and AST. Mechanistically, Mtu1 deficiency resulted in a loss of 2-thiolation in mt-tRNAs, which led to a marked impairment of mitochondrial translation. Consequently, Mtu1LKO mice exhibited severe disruption of mitochondrial membrane integrity and a broad decrease in respiratory complex activities in the hepatocytes. Interestingly, mitochondrial dysfunction induced signaling pathways related to mitochondrial proliferation and the suppression of oxidative stress. The present study demonstrates that Mtu1-dependent 2-thiolation of mt-tRNA is indispensable for mitochondrial translation and that Mtu1 deficiency is a primary cause of RILF. In addition, Mtu1 deficiency is associated with multiple cytoprotective pathways that might prevent catastrophic liver failure and assist in the recovery from liver injury.
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Yong
http://orcid.org/0000-0001-9840-940X
Y
Wu
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.|Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Kawaguchi, Japan.
Fan-Yan
FY
Wei
Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo, Japan.
Layla
http://orcid.org/0000-0002-4565-3780
L
Kawarada
Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo, Japan.
Takeo
T
Suzuki
Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
Kimi
K
Araki
Department of Cell Pathology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Yoshihiro
Y
Komohara
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Atsushi
A
Fujimura
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Taku
http://orcid.org/0000-0001-5556-8179
T
Kaitsuka
Department of Cell Pathology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Motohiro
M
Takeya
Department of Molecular Genetics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Yuichi
Y
Oike
Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo, Japan.
Tsutomu
T
Suzuki
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Kazuhito
K
Tomizawa
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