Mitochondrial DNA Integrity: Role in Health and Disease

Abstract

As the primary cellular location for respiration and energy production, mitochondria serve in a critical capacity to the cell. Yet, by virtue of this very function of respiration, mitochondria are subject to constant oxidative stress that can damage one of the unique features of this organelle, its distinct genome. Damage to mitochondrial DNA (mtDNA) and loss of mitochondrial genome integrity is increasingly understood to play a role in the development of both severe early-onset maladies and chronic age-related diseases. In this article, we review the processes by which mtDNA integrity is maintained, with an emphasis on the repair of oxidative DNA lesions, and the cellular consequences of diminished mitochondrial genome stability.

Keywords: aging; base excision repair; metabolic syndrome; mitochondrial DNA; neurodegenerative diseases.

Figure 1

Mechanisms of inheritance of mtDNA mutations. Each mitochondrion consists of multiple copies of mtDNA, some of which may harbor harmful mutations. Upon mitochondrial fission, fusion, or mtDNA replication, these mtDNA molecules may be randomly segregated to daughter mitochondria, resulting in either reduced or increased levels of heteroplasmy. The contribution of heteroplasmy to disease development is difficult to study, as the disease threshold for each mutation may be different and may lead to a range of clinical and sub-clinical phenotypes. (Green ovals = functional mitochondria; red = dysfunctional; blue = suboptimal function).

Figure 2

Base Excision Repair (BER) in mitochondria. Generation of free radicals induces DNA lesions in the form of oxidized bases, affecting base-pairing properties. Oxidative lesions are repaired via the BER pathway. BER is initiated by the activity of DNA glycosylases such as monofunctional glycosylases which recognize and cleave the N-glycosidic bond between the modified base and sugar, creating an abasic site and bifunctional glycosylases which have an additional intrinsic Apurinic/Apyrimidinic (AP)lyase activity. The incision of the AP site occurs via β elimination or β-δ elimination which is further processed by APE1 or PNKP, followed by gap-filling by DNA pol gamma (PolG). Once the AP site has been processed and the correct nucleotide recruited by PolG, the free DNA ends are ligated by DNA ligase III (LIG3).