The Complicated Nature of Somatic mtDNA Mutations in Aging

Abstract

Mitochondria are the main source of energy used to maintain cellular homeostasis. This aspect of mitochondrial biology underlies their putative role in age-associated tissue dysfunction. Proper functioning of the electron transport chain (ETC), which is partially encoded by the extra-nuclear mitochondrial genome (mtDNA), is key to maintaining this energy production. The acquisition of de novo somatic mutations that interrupt the function of the ETC have long been associated with aging and common diseases of the elderly. Yet, despite over 30 years of study, the exact role(s) mtDNA mutations play in driving aging and its associated pathologies remains under considerable debate. Furthermore, even fundamental aspects of age-related mtDNA mutagenesis, such as when mutations arise during aging, where and how often they occur across tissues, and the specific mechanisms that give rise to them, remain poorly understood. In this review, we address the current understanding of the somatic mtDNA mutations, with an emphasis of when, where, and how these mutations arise during aging. Additionally, we highlight current limitations in our knowledge and critically evaluate the controversies stemming from these limitations. Lastly, we highlight new and emerging technologies that offer potential ways forward in increasing our understanding of somatic mtDNA mutagenesis in the aging process.

Mitochondrial DNA Repair in Neurodegenerative Diseases and Ageing

“…Interestingly, mtDNA mutations have been associated with age through increased numbers of mutated mitochondria building up rather than individual mitochondria becoming increasingly damaged. The presence of random mutations even in young healthy individuals supports this hypothesis [ 93 ]. Specific point mutations and deletions in mtDNA are present during early development and even in germline cells [ 90 , 94 ].…”

Long-Term Persistence of Mitochondrial DNA Instability in HIV-Exposed Uninfected Children during and after Exposure to Antiretroviral Drugs and HIV

“…The first described mtDNA deletion, namely the common ∆4977bp mtDNA deletion, accumulates according to age, especially in post-mitotic tissues [ 36 , 37 ]; however, so far, only a few studies have analyzed mtDNA deletion data via a deep sequencing approach by age group [ 11 , 12 ]. These studies also showed an increasing proportion of mtDNA rearrangements with age as well as with carcinogenesis [ 8 ].…”

Heterogenous Differences in Cellular Senescent Phenotypes in Pre-Eclampsia and IUGR following Quantitative Assessment of Multiple Biomarkers of Senescence

“…Premature cellular senescence can be classified by activation of a DNA damage response pathway and its associated signaling kinases which culminate in the stimulation of cell cycle inhibitors, such as p16INK4a, p21/p53, and p27, reduction in cellular proliferation, and loss of Lamin-B activity, which is a marker of the altered enlarged and flattened morphology of senescent cells [ 9 ]. Moreover, the accumulation of mitochondrial DNA (mtDNA), as a result of ROS inducing damage and strand breaks, has been associated with premature onset of ageing in both in vivo and in vitro models, with higher susceptibility to mtDNA mutagenesis [ 10 , 11 ]. Activation of a senescence-associated secretory phenotype (SASP) incorporating a core set of cytokines, such as IL-6, IL-8, IL-13, IGFBPs, and MMPs, results in accumulated senile cells creating a pro-inflammatory microenvironment that indicates establishment of senescence [ 12 ].…”