Maternally inherited diabetes is associated with a homoplasmic T10003C mutation in the mitochondrial tRNAGly gene

• Diabetes only presented in the maternal lineage of four-generation Chinese pedigree.
• The homoplasmic diabetes-associated tRNAGly T10003C mutation altered structure and function of this tRNA.
• Mutant cells carrying the T10003C mutation exhibited reduced levels of tRNAGly, mitochondrial translation and respiration.
• Our data suggested that the T10003C mutation caused diabetes.

In this report, we investigate molecular pathogenic mechanism of a diabetes-associated homoplasmic mitochondrial tRNA mutation in a Han Chinese family with maternally transmitted diabetes mellitus. Of 10 adult matrilineal relatives, 5 individuals suffered from diabetes (4 subjects with only diabetes, one subject with both diabetes and hearing impairment), while other five matrilineal relatives (one with hearing loss) had glucose intolerance. The average age at onset of diabetes in matrilineal relatives was 50 years. Molecular analysis of their mitochondrial genomes identified the novel homoplasmic T10003C mutation in the tRNAGly gene belonging to haplogroup M11b. The T10003C mutation is expected to form a base-pairing (13C-22G) at the highly conserved D-stem of tRNAGly, thereby affecting secondary structure and function of this tRNA. A tRNA Northern analysis revealed that the T10003C mutation caused ~ 70% reduction in the steady-state level of tRNAGly. An in vivo translation analysis showed ~ 33% reduction in the rate of mitochondrial translation in mutant cells. Oxygen consumption analysis showed the defects in overall respiratory capacity or the ATP-linked, proton leak, and maximal respiration in mutant cells. As a result, the cellular energy deficiency contributes to the development of diabetes in subjects carrying the T10003C mutation. These data provide the first direct evidence that the tRNAGly mutation might be associated with diabetes. Thus, our findings may provide new insights into the understanding of pathophysiology of maternally inherited diabetes.