Mitochondrial DNA Toxicity in Forebrain Neurons Causes Apoptosis, Neurodegeneration, and Impaired Behavior

Abstract

Mitochondrial dysfunction underlying changes in neurodegenerative diseases is often associated with apoptosis and a progressive loss of neurons, and damage to the mitochondrial genome is proposed to be involved in such pathologies. In the present study we designed a mouse model that allows us to specifically induce mitochondrial DNA toxicity in the forebrain neurons of adult mice. This is achieved by CaMKII␣-regulated inducible expression of a mutated version of the mitochondrial UNG DNA repair enzyme (mutUNG1). This enzyme is capable of removing thymine from the mitochondrial genome. We demonstrate that a continual generation of apyrimidinic sites causes apoptosis and neuronal death. These defects are associated with behavioral alterations characterized by increased locomotor activity, impaired cognitive abilities, and lack of anxietylike responses. In summary, whereas mitochondrial base substitution and deletions previously have been shown to correlate with premature and natural aging, respectively, we show that a high level of apyrimidinic sites lead to mitochondrial DNA cytotoxicity, which causes apoptosis, followed by neurodegeneration.A variety of both exogenous and endogenous reactive compounds present a constant threat to the integrity of DNA in living cells. DNA damage introduced by such compounds can lead to high and deleterious mutation rates as well as DNA cytotoxicity, both to the nuclear and the mitochondrial genome. This has triggered the evolution of several different DNA repair pathways (28). One is the base excision repair (BER) pathway, which repairs small base alterations that do not distort the DNA helix. Repair of such highly abundant lesions by BER is performed by a multistep process that is initiated by a damage-specific DNA glycosylase, which removes the damaged base. One of these glycosylases is uracil-DNA glycosylase (UDG), which acts to preserve the genome by removing mutagenic uracil residues from the DNA. This glycosylase, as well as the OGG1 glycosylase that is specialized for the removal of oxidized bases, exists in a nuclear and mitochondrial splice form (1,11,37,45). Accordingly, BER of a variety of lesions has been observed in mitochondria (26,31).Damage to the mitochondrial DNA (mtDNA) can cause respiratory chain deficiency and lead to disorders that have varied phenotypes (35,41). Many involve neurological features that are often associated with cell loss within specific brain regions. These pathologies, along with the increasing evidence of a decline in mitochondrial function with aging, have raised speculation that key changes in mitochondrial DNA sequences and functions could have a vital role in age-related neurodegenerative diseases (41). This has also been studied in several model organisms. Mouse models with respiratory chain deficient dopamine neurons have demonstrated adult onset Parkinsonism phenotype (16), and cell death induced by mitochondrial toxicity is likely to underlie Alzheimer disease (32). Mitochondrial oxidative stress and accumulation of mtDNA damage ar...

Prolonged lifespan with enhanced exploratory behavior in mice overexpressing the oxidized nucleoside triphosphatase hMTH1

“…and this has been linked to an improved ability to cope with environmental stressors and an enhanced immune response (PerezAlvarez et al, 2005;Yee et al, 2008;Cavigelli et al, 2010;Aguilera, 2011). Decreased anxiety, in association however with learning impairment and enhanced locomotor activity, has been reported in a mouse model of defective mitochondrial DNA repair expressing a mutant version of the mitochondrial UNG gene (Lauritzen et al, 2010). The extended behavioral analysis performed in our study clearly indicates that the baseline motor activity of hMTH1 mice is unaltered.…”

Mitochondrial DNA Oxidative Damage and Repair in Aging and Alzheimer's Disease

“…The contradictory observations reported in human and mice AD brains can be easily explained by the fact that the disease process in 3 · Tg-AD mice is the result of a genetic manipulation, as those animals harbor the human amyloid precursor Swedish mutation, presenilin-1 M146V (PS1(M146V)) knockin mutation, and tau (P301L) mutation; whereas in sporadic AD patients, mitochondria malfunctioning and oxidative stress are considered causative agents (155). Notably, rodents that were engineered to express an inducible mutant form of UDG1 show a decline in cognitive performance, as evaluated by the Morris water maze test (102). Furthermore, and similarly to that described in AD (198), rodents expressing mutant UDG1 also display abnormal mitochondrial dynamics (101), which supports the idea that impaired BER machinery may also play a role in AD.…”

Impaired dynamics and function of mitochondria caused by mtDNA toxicity leads to heart failure

“…Doxycycline was administered as previously described (28). Transgenic founders were selected by investigating luciferase expression in hearts and other organs utilizing in vivo and ex vivo imaging.…”