Xu L, Liu MT, He XM, Zhang SR, Yu DJ, Ding Y. Type 2 diabetes mellitus may be associated with a novel mitochondrial tRNAThr/tRNAPro mutation. World J Diabetes 2026; 17(4): 115842 [DOI: 10.4239/wjd.v17.i4.115842]
Corresponding Author of This Article
Yu Ding, MD, Associate Professor, Department of Clinical Laboratory, Hangzhou First People’s Hospital, No. 261 Huansha Road, Hangzhou 310006, Zhejiang Province, China. dingyu_zj@126.com
Research Domain of This Article
Genetics & Heredity
Article-Type of This Article
Basic Study
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Apr 15, 2026 (publication date) through Apr 14, 2026
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Journal Information of This Article
Publication Name
World Journal of Diabetes
ISSN
1948-9358
Publisher of This Article
Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
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Xu L, Liu MT, He XM, Zhang SR, Yu DJ, Ding Y. Type 2 diabetes mellitus may be associated with a novel mitochondrial tRNAThr/tRNAPro mutation. World J Diabetes 2026; 17(4): 115842 [DOI: 10.4239/wjd.v17.i4.115842]
Liang Xu, Meng-Ting Liu, The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China
Xiu-Mei He, Department of Clinical Laboratory, Jiande First People’s Hospital, Hangzhou 311600, Zhejiang Province, China
Shun-Rong Zhang, Department of Geriatrics, Hangzhou First People’s Hospital, Hangzhou 310006, Zhejiang Province, China
Dao-Jun Yu, Yu Ding, Department of Clinical Laboratory, Hangzhou First People’s Hospital, Hangzhou 310006, Zhejiang Province, China
Co-first authors: Liang Xu and Meng-Ting Liu.
Co-corresponding authors: Dao-Jun Yu and Yu Ding.
Author contributions: Xu L and Liu MT performed the genetic and cellular experiments and are co-first authors of this manuscript; He XM performed molecular and statistical analyses; Zhang SR collected samples and controls; Yu DJ and Ding Y designed the study and drafted the manuscript and are co-corresponding authors of this manuscript; all authors read the manuscript.
Supported by the Key Project of Natural Science Foundation of Zhejiang Province, No. LZ22H190002; Hangzhou Joint Fund of the Zhejiang Provincial Natural Science Foundation of China, No. LHZY24H020002; Key Project of Hangzhou Bureau of Science and Technology, No. 202204A01; Zhejiang Provincial Medicine and Health Science Foundation, No. WKJ-ZJ-2514; and the Construction Fund of Key Medical Disciplines of Hangzhou, Laboratory Diagnostics, No. 2025HZZD01.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Hangzhou First People’s Hospital (approval No. KY-20240327-0100-01).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: The datasets for this study will be available from the corresponding authors upon reasonable request.
Corresponding author: Yu Ding, MD, Associate Professor, Department of Clinical Laboratory, Hangzhou First People’s Hospital, No. 261 Huansha Road, Hangzhou 310006, Zhejiang Province, China. dingyu_zj@126.com
Received: October 28, 2025 Revised: December 17, 2025 Accepted: March 5, 2026 Published online: April 15, 2026 Processing time: 169 Days and 6.7 Hours
Abstract
BACKGROUND
Mutations in mitochondrial (mt) transfer RNAs (tRNAs) represent a significant genetic risk factor for type 2 diabetes mellitus, though their underlying pathogenic mechanisms remain incompletely elucidated.
AIM
To investigate the potential pathogenic role of a novel diabetes related mt-tRNAThr/tRNAPro C15954T mutation.
METHODS
A four-generation Han Chinese pedigree exhibiting maternal inheritance of type 2 diabetes mellitus was underwent clinical, genetic and molecular analyses. Mitochondrial genome mutations were screened via polymerase chain reaction-Sanger sequencing, and mt function was determined in cybrid cells derived from four affected individuals carrying the m.C15954T mutation and four control subjects without the mutation.
RESULTS
Matrilineal relatives within the pedigree displayed heterogeneous clinical manifestations of type 2 diabetes mellitus, with the age of onset ranging from 41 years to 66 years (mean: 52 years). Whole mitochondrial genome sequencing identified a novel m.C15954T mutation located adjacent to the mt-tRNAThr and mt-tRNAPro genes. This mutation affects a phylogenetically conserved nucleotide which is critical for tRNA 3’-end processing and function. Biochemical assays demonstrated that cybrids carrying the m.C15954T mutation reduced tRNAThr and tRNAPro steady-state levels. In addition, the mt DNA copy number, adenosine triphosphate production, mt membrane potential, mt-RNA transcription, oxidative phosphorylation enzyme activities were markedly decreased. In contrast, reactive oxygen species levels were elevated.
CONCLUSION
These findings indicate that the m.C15954T mutation leads to mt dysfunctions and contributes to the pathogenesis of type 2 diabetes in this Chinese pedigree.
Core Tip: This study reports a Han Chinese pedigree with maternally inherited type 2 diabetes mellitus. We identified a novel mitochondrial (mt) C15954T mutation located in the intergenic spacer between the mt-tRNAThr and mt-tRNAPro genes. Phylogenetic analysis revealed that the nucleotide at position 15954 is highly conserved across species, suggesting a potential role in the 3’ end processing of both tRNAThr and tRNAPro. Using trans-mitochondrial cybrid models, we demonstrated that the m.C15954T mutation leads to impaired mt-transfer RNA metabolism and significant mt dysfunction. These findings indicate that the m.C15954T mutation may contribute to the pathogenesis of diabetes in this pedigree.
