Mitochondrial DNA polymorphisms in COX1 affect the lifespan of Caenorhabditis elegans through nuclear gene dct-15

Abstract

Mutations in the mitochondrial DNA (mtDNA) are closely related to age and age-related complex diseases, but the exact regulatory mechanism of mtDNA natural variation or polymorphism and ageing remains unclear. Recently, nuclear genes that regulate mitochondrial functions and thereby influence ageing have been widely studied. In this study, the relationship between the retrograde communication from the mitochondria to the nucleus and its ultimate effect on ageing has been elucidated. This study found that the natural variations in COX1 of the mitochondria in the Caenorhabditis elegans population do not correlate with multiple phenotypes, except for a mild correlation with lifespan. After excluding the differences in the nuclear genome, the correlation between natural mitochondrial variation and lifespan increased significantly. Moreover, mtDNA variation downregulated the nuclear dct-15 gene expression, which consequently reduced the lifespan, development rate and motility of C. elegans. dct-15 mutations decreased mitochondria copy number but increased ATP content and mitochondrial ultrastructure. Thus, the results indicated that dct-15 interacted with the mitochondrial DNA polymorphisms in COX1 and is associated with ageing. Finally, bioinformatic analyses revealed that mtDNA variation regulated the structural constituent of the cuticle via dct-15 and suggested that the structural constituent of the cuticle could have an important role in the development and ageing processes. These results provide insights into the mtDNA mechanism that can alter the nuclear gene and thereby regulate ageing and ageing-related diseases.