Abstract
Recently, mitochondrial-nuclear interaction in aging has been widely studied. However, the nuclear genome controlled by natural mitochondrial variations that influence aging has not been comprehensively understood so far. We hypothesized that mitochondrial polymorphisms could play critical roles in the aging process, probably by regulation of the whole-transcriptome expression. Our results showed that mitochondria polymorphisms not only decreased the mitochondrial mass but also miRNA, lncRNA, mRNA, circRNA and metabolite profiles. Furthermore, most genes that are associated with mitochondria show age-related expression features (P = 3.58E-35). We also constructed a differentially expressed circRNA-lncRNA-miRNA-mRNA regulatory network and a ceRNA network affected by the mitochondrial variations. In addition, Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the genes affected by the mitochondrial variation were enriched in metabolic activity. We finally constructed a multi-level regulatory network with aging which affected by the mitochondrial variation in Caenorhabditis elegans. The interactions between these genes and metabolites have great values for further aging research. In sum, our findings provide new evidence for understanding the molecular mechanisms of how mitochondria influence aging.
Highlights
Mitochondria functions as an essential energy provider for eukaryotic cells and could occupy up to 20% cell volume, which makes it vital in cell growth and aging
We proposed a hypothesis that longevity or aging as a complex trait is likely to be controlled by nuclear gene expression network, which could be further regulated by natural variations in mitochondrial DNA
Both mitochondrial and nuclear genomes correlate with the quantitative traits of development and lifespan of C. elegans
Summary
Mitochondria functions as an essential energy provider for eukaryotic cells and could occupy up to 20% cell volume, which makes it vital in cell growth and aging. Mounting evidence suggests that the mitochondrial dysfunction is a central event of aging processes [1], some studies showed that mitochondrial DNA polymorphisms are associated with human longevity [2, 3]. Nuclear genes have been reported to be capable of altering mitochondrial functions with severe biological dysfunction [4], and the mtDNA genotype vary among www.aging-us.com different nuclear allelic backgrounds could influence healthy ageing [5]. Most studies of regulatory mechanism of the mitochondrial function have focused on nuclear genes. A recent study showed that the mitochondrial-encoded peptide could regulate nuclear gene expression in response to metabolic stress [6]. Comprehensive understanding of how mitochondria regulate the nuclear genome and influence aging is still lacking
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