Yu XJ, Ding Y. Maternally inherited type 2 diabetes mellitus may be associated with mitochondrial tRNAThr mutations. World J Diabetes 2026; 17(8): 121165 [DOI: 10.4239/wjd.121165]
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
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Endocrinology & Metabolism
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Yu XJ, Ding Y. Maternally inherited type 2 diabetes mellitus may be associated with mitochondrial tRNAThr mutations. World J Diabetes 2026; 17(8): 121165 [DOI: 10.4239/wjd.121165]
World J Diabetes. Aug 15, 2026; 17(8): 121165 Published online Aug 15, 2026. doi: 10.4239/wjd.121165
Maternally inherited type 2 diabetes mellitus may be associated with mitochondrial tRNAThr mutations
Xue-Jiao Yu, Yu Ding
Xue-Jiao Yu, Clinical Laboratory, Quzhou People’s Hospital, the Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou 324000, Zhejiang Province, China
Yu Ding, Department of Clinical Laboratory, Hangzhou First People’s Hospital, Hangzhou 310006, Zhejiang Province, China
Author contributions: Yu XJ was responsible for materials, data collection and processing, analysis, and interpretation; Ding Y was responsible for the study concept and design, supervision, literature review, manuscript writing, and critical review; Yu XJ and Ding Y were responsible for funding acquisition; all authors read and approved the final version of the manuscript to be published.
AI contribution statement: No AI tool was involved in the generation of research data, interpretation of results, or formulation of conclusions.
Supported by Quzhou Bureau of Science and Technology (No. 2025K044), Hangzhou Joint Fund of the Zhejiang Provincial Natural Science Foundation of China (No. LHZY24H020002), and Hangzhou Municipal Health Commission (No. ZD20220010).
Institutional review board statement: The study protocol, including the informed consent forms and the consent for publication of case details, was approved by the Ethics Committee of Hangzhou First People’s Hospital (Approval No. KY-20240327-0100-01).
Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.
Data sharing statement: The datasets used and analyzed during the current study are available from the corresponding author (dingyu_zj@126.com) 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: March 19, 2026 Revised: May 10, 2026 Accepted: July 3, 2026 Published online: August 15, 2026 Processing time: 140 Days and 5.9 Hours
Abstract
BACKGROUND
Mutations in mitochondrial DNA, especially those in mitochondrial tRNA genes, are closely related to type 2 diabetes mellitus (T2DM). However, the underlying molecular mechanisms remain largely unknown.
AIM
To investigate the potential associations between mitochondrial tRNA mutations and T2DM.
METHODS
Two Han Chinese families with T2DM underwent clinical, genetic, and biochemical analyses, and mutations in the entire mitochondrial genome were screened in the matrilineal relatives of these pedigrees. Mitochondrial function was assessed in cybrid cell lines harboring tRNAThr mutations.
RESULTS
The matrilineal relatives of these pedigrees expressed variable clinical phenotypes, including deafness, visual loss, and renal failure. Sequence analysis of the entire mitochondrial genomes revealed a set of genetic polymorphisms and three possible pathogenic mutations: tRNAThr A15951G, G15930A, and G15927A. The A15951G mutation was located adjacent to the 3’ end of tRNAThr, abolishing a conserved 2T-71A base-pairing. The G15930A mutation occurred at a conserved position in the variable region of tRNAThr, whereas the G15927A mutation disrupted the 28C-42G base pairing in the anticodon stem of tRNAThr. Thus, it can be speculated that these mutations may alter the tRNA structure and function. Using cybrid cell lines derived from five patients with tRNAThr mutations and four controls without these mutations, we found that mutant cells exhibited significantly lower adenosine triphosphate levels, membrane potential, and NAD+/NADH ratio, whereas reactive oxygen species were increased significantly, suggesting that the A15951G, G15930A, and G15927A mutations led to mitochondrial dysfunction, which may contribute to the progression of T2DM.
CONCLUSION
Our study revealed that tRNAThr is a hotspot for pathogenic mutations associated with T2DM. Screening for tRNAThr mutations is recommended for the prevention and diagnosis of mitochondrial diabetes.
Core Tip: This study identified three mitochondrial tRNAThr mutations—G15927A, G15930A, and A15951G—in two Han Chinese pedigrees with maternally inherited type 2 diabetes mellitus. These mutations were associated with variable clinical phenotypes, including deafness, visual impairment, and renal failure. Functional analyses using cybrid cell lines revealed that these mutations lead to mitochondrial dysfunction, as evidenced by reduced adenosine triphosphate production, decreased mitochondrial membrane potential, lower NAD+/NADH ratio, and increased reactive oxygen species levels. Our findings identify tRNAThr as a mutational hotspot in mitochondrial diabetes and support the inclusion of these mutations in genetic screening strategies for the early diagnosis and prevention of type 2 diabetes mellitus.
