Behavioral and metabolic characterization of heterozygous and homozygous POLG mutator mice

Dai, Ying; Kiselak, Tomas; Clark, Joanne; Clore, Elizabeth L.; Zheng, Kangni; Cheng, Allen A.; Kujoth, Gregory C.; Prolla, Tomas A.; Maratos–Flier, Eleftheria; Simon, David K.

doi:10.1016/j.mito.2013.03.006

Cited by 39 publications

(43 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, a significant decrease in complex IV (COX) activities was observed in skeletal muscles of Polg +/D257A mice at 96 weeks (Fig. S8) similar to that in cortex of Polg +/D257A mice in previous report 37…”

Section: Resultssupporting

confidence: 85%

Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions

Fuke

Kametani

Yamada

et al. 2014

Ann Clin Transl Neurol

Self Cite

View full text Add to dashboard Cite

ObjectiveMutations in nuclear-encoded mitochondrial DNA (mtDNA) polymerase (POLG) are known to cause autosomal dominant chronic progressive external ophthalmoplegia (adCPEO) with accumulation of multiple mtDNA deletions in muscles. However, no animal model with a heterozygous Polg mutation representing mtDNA impairment and symptoms of CPEO has been established. To understand the pathogenic mechanism of CPEO, it is important to determine the age dependency and tissue specificity of mtDNA impairment resulting from a heterozygous mutation in the Polg gene in an animal model.MethodsWe assessed behavioral phenotypes, tissue-specific accumulation of mtDNA deletions, and its age dependency in heterozygous PolgD257A knock-in mice carrying a proofreading-deficient mutation in the Polg.ResultsHeterozygous PolgD257A knock-in mice exhibited motor dysfunction in a rotarod test. Polg+/D257A mice had significant accumulation of multiple mtDNA deletions, but did not show significant accumulation of point mutations or mtDNA depletion in the brain. While mtDNA deletions increased in an age-dependent manner regardless of the tissue even in Polg+/+ mice, the age-dependent accumulation of mtDNA deletions was enhanced in muscles and in the brain of Polg+/D257A mice.InterpretationHeterozygous PolgD257A knock-in mice showed tissue-specific, age-dependent accumulation of multiple mtDNA deletions in muscles and the brain which was likely to result in neuromuscular symptoms. Polg+/D257A mice may be used as an animal model of adCPEO associated with impaired mtDNA maintenance.

show abstract

Section: Resultssupporting

confidence: 85%

Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions

Fuke

Kametani

Yamada

et al. 2014

Ann Clin Transl Neurol

Self Cite

View full text Add to dashboard Cite

show abstract

“…In support of this idea, we would reason that the POLG mouse progresses along a gradient of increasing stress from mitochondrial mutations as it ages, which at a certain stage will tip the scales between the starvation-like benefits mediated by FGF21 at a young age to unavoidable metabolic dysfunction. Indeed, the pathological metabolic state evident in old POLG mice has been described by recent studies (31,32). However, the possibility that chronic mild mitochondrial stress also contributes to the pathologic side of the POLG phenotype must also not be discounted.…”

Section: Discussionmentioning

confidence: 94%

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

Wall

Whyte

Suh

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Mitochondria are highly adaptable organelles that can facilitate communication between tissues to meet the energetic demands of the organism. However, the mechanisms by which mitochondria can nonautonomously relay stress signals remain poorly understood. Here we report that mitochondrial mutations in the young, preprogeroid polymerase gamma mutator (POLG) mouse produce a metabolic state of starvation. As a result, these mice exhibit signs of metabolic imbalance including thermogenic defects in brown adipose tissue (BAT). An unexpected benefit of this adaptive response is the complete resistance to diet-induced obesity when POLG mice are placed on a high-fat diet (HFD). Paradoxically, HFD further increases oxygen consumption in part by inducing thermogenesis and mitochondrial biogenesis in BAT along with enhanced expression of fibroblast growth factor 21 (FGF21). Collectively, these findings identify a mechanistic link between FGF21, a long-known marker of mitochondrial disease, and systemic metabolic adaptation in response to mitochondrial stress.

show abstract

“…Cryoprotected brains were cut on a freezing microtome and immunostained as previously described (Dai et al 2013). Briefly, striatal sections were cut at 30 mm thickness and then immunostained with a primary mouse antibody against TH (1:1000; Sigma, Cat.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, heterozygous mutant POLG mice (designated POLG +/mut mice) show no “overt” phenotype at any age despite also having levels of somatic mtDNA mutations even at young ages that are higher than in normal aged mice (Vermulst et al, 2007). These data have been interpreted as evidence against a role for somatic mtDNA mutations during normal aging, although we recently reported that older POLG +/mut mice do indeed have metabolic deficits and decreased protein levels of mitochondrial electron transport chain complexes and complex IV activity in their brain (Dai et al, 2013). Moreover, POLG mut/mut mice also have decreased levels of peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) associated with significant mtDNA depletion (Trifunovic et al 2004; Safdar et al, 2011) and correspondingly show impaired mitochondrial bioenergetics with a profound reduction in expression of gene sets associated with mitochondrial function (Hiona et al, 2010; Safdar et al 2011).…”

Section: Introductionmentioning

confidence: 99%

“…We recently reported that substantia nigra (SN) neurons accumulate very high levels of somatic mtDNA mutations during early stages of PD, similar in some neurons to levels demonstrated to cause functional impairment in the POLG mut/mut mice (Lin et al, 2012). At older ages, POLG mut/mut mice demonstrate significant reductions in striatal dopaminergic terminals as well as deficits in motor function compared to wild type (WT) littermates (Dai et al 2013). Thus, in addition to contributing to neuronal vulnerability to environmental stressors, somatic mtDNA mutations also may play a role in age-related neurodegenerative diseases such as PD.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Somatic mitochondrial DNA mutations do not increase neuronal vulnerability to MPTP in young POLG mutator mice

Dai

Clark

Zheng

et al. 2014

Neurotoxicology and Teratology

Self Cite

View full text Add to dashboard Cite

Mitochondrial DNA (mtDNA) mutations are hypothesized to play a pathogenic role in aging and age-related neurodegenerative diseases such as Parkinson’s disease (PD). In support of this, high levels of somatic mtDNA mutations in “POLG mutator” mice carrying a proofreading-deficient form of mtDNA polymerase γ (PolgD257A) lead to a premature aging phenotype. However, the relevance of this finding to the normal aging process has been questioned as the number of mutations is greater even in young POLG mutator mice, which show no overt phenotype, than levels achieved during normal aging in mice. Vulnerability of dopaminergic neurons to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) increases with age, and we hypothesized that this may result in part from the accumulation with age of somatic mtDNA mutations. If correct, then levels of mutations in young (2~3 month old) POLG mutator mice should be sufficient to increase vulnerability to MPTP. In contrast, we find that susceptibility to MPTP in both heterozygous and homozygous POLG mutator mice at this young age is not different from that of wild type littermate controls as measured by levels of tyrosine hydroxylase positive (TH+) striatal terminals, striatal dopamine and its metabolites, a marker of oxidative damage, or stereological counts of TH+ and total substantia nigra neurons. These unexpected results do not support the hypothesis that somatic mtDNA mutations contribute to the age-related vulnerability of dopaminergic neurons to MPTP. It remains possible that somatic mtDNA mutations influence vulnerability to other stressors, or require additional time for the deleterious consequences to manifest. Furthermore, the impact of the higher levels of mutations present at older ages in these mice was not assessed in our study, although a prior study also failed to detect an increase in vulnerability to MPTP in older mice. With these caveats, the current data do not provide evidence for a role of somatic mtDNA mutations in determining the vulnerability to MPTP.

show abstract

Behavioral and metabolic characterization of heterozygous and homozygous POLG mutator mice

Cited by 39 publications

References 49 publications

Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions

Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

Somatic mitochondrial DNA mutations do not increase neuronal vulnerability to MPTP in young POLG mutator mice

Contact Info

Product

Resources

About