Abstract
Mitochondrial defects are implicated in aging and in a multitude of age-related diseases, such as cancer, heart failure, Parkinson’s disease, and Huntington’s disease. However, it is still unclear how mitochondrial defects arise under normal physiological conditions. Mitochondrial DNA (mtDNA) deletions caused by direct repeats (DRs) are implicated in the formation of mitochondrial defects, however, mitochondrial DRs show relatively weak (Pearson’s r = −0.22, p<0.002; Spearman’s ρ = −0.12, p = 0.1) correlation with maximum lifespan (MLS). Here we report a stronger correlation (Pearson’s r = −0.55, p<10–16; Spearman’s ρ = −0.52, p<10–14) between mitochondrial inverted repeats (IRs) and lifespan across 202 species of mammals. We show that, in wild type mice under normal conditions, IRs cause inversions, which arise by replication-dependent mechanism. The inversions accumulate with age in the brain and heart. Our data suggest that IR-mediated inversions are more mutagenic than DR-mediated deletions in mtDNA, and impose stronger constraint on lifespan. Our study identifies IR-induced mitochondrial genome instability during mtDNA replication as a potential cause for mitochondrial defects.
Highlights
Mitochondria are responsible for generating most of ATP in a eukaryotic cell
We report that mitochondrial inverted repeats (IRs) have a stronger negative correlation with animal lifespan than direct repeats (DRs), and that IRs induce mitochondrial genome instability during Mitochondrial DNA (mtDNA) replication and cause mtDNA inversions that accumulate with age in mice
We analyzed the correlation between mtDNA IRs and lifespans for all animal species that had both mitochondrial genome reference sequences in NCBI and lifespan information in
Summary
Mitochondria are responsible for generating most of ATP in a eukaryotic cell. Mitochondria have their own genome, which is a small DNA molecule between 13 kb and 26 kb in most animals, encoding central components of the electron transport chain and some rRNAs and tRNAs. Mitochondrial free radical theory of aging proposes that reactive oxygen species that are produced in the mitochondria, cause damage to macromolecules such as proteins, lipids and mtDNA and organisms age as they accumulate free radical damage over time over time [3]. This theory is supported by the findings that the catalase targeted to mitochondria attenuates aging in mice [13]. We report that mitochondrial inverted repeats (IRs) have a stronger negative correlation with animal lifespan than DRs, and that IRs induce mitochondrial genome instability during mtDNA replication and cause mtDNA inversions that accumulate with age in mice
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