Abstract
Deletion mutations within mitochondrial DNA (mtDNA) have been implicated in degenerative and aging related conditions, such as sarcopenia and neuro-degeneration. While the precise molecular mechanism of deletion formation in mtDNA is still not completely understood, genome motifs such as direct repeat (DR) and stem-loop (SL) have been observed in the neighborhood of deletion breakpoints and thus have been postulated to take part in mutagenesis. In this study, we have analyzed the mitochondrial genomes from four different mammals: human, rhesus monkey, mouse and rat, and compared them to randomly generated sequences to further elucidate the role of direct repeat and stem-loop motifs in aging associated mtDNA deletions. Our analysis revealed that in the four species, DR and SL structures are abundant and that their distributions in mtDNA are not statistically different from randomized sequences. However, the average distance between the reported age associated mtDNA breakpoints and their respective nearest DR motifs is significantly shorter than what is expected of random chance in human (p<10−4) and rhesus monkey (p = 0.0034), but not in mouse (p = 0.0719) and rat (p = 0.0437), indicating the existence of species specific difference in the relationship between DR motifs and deletion breakpoints. In addition, the frequencies of large DRs (>10 bp) tend to decrease with increasing lifespan among the four mammals studied here, further suggesting an evolutionary selection against stable mtDNA misalignments associated with long DRs in long-living animals. In contrast to the results on DR, the probability of finding SL motifs near a deletion breakpoint does not differ from random in any of the four mtDNA sequences considered. Taken together, the findings in this study give support for the importance of stable mtDNA misalignments, aided by long DRs, as a major mechanism of deletion formation in long-living, but not in short-living mammals.
Highlights
Mitochondria are intracellular organelles that carry multiple copies of circular double stranded DNA
The analysis of all four mitochondrial DNA (mtDNA) sequences revealed an abundance of direct repeats of various sizes in the mitochondrial genome, where roughly 80% of the DRs resided in the major arc
Accumulation of mitochondrial DNA deletions is implicated in many degenerative and age-related diseases in humans, including Parkinson’s disease, Kearn-Sayre syndrome, and sarcopenia [1,21,22,23]. Such mutations have been attributed to the misalignment of mtDNA during replication or repair, a hypothesis that was supported by frequent observations of genome motifs, direct repeat, flanking or near the deletion breakpoints in human and other species [11,24,25]
Summary
Mitochondria are intracellular organelles that carry multiple copies of circular double stranded DNA. High intracellular levels of mtDNA molecules with such deletions can result in respiratory chain dysfunction and ATP deficiency, leading to pathologies such as muscle fiber atrophy in sarcopenia, and have been proposed as a major factor for the decline in physiological functions in aged tissues [5,6]. Understanding how such deletions occur is essential to frame intervention strategies against pathogenic consequences of aging-associated mitochondrial dysfunction. Earlier studies have shown that a majority of deletion mutations in human mtDNA are either exactly or proximately flanked by DRs [9,10,11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
