Somatic mitochondrial DNA mutations in early parkinson and incidental lewy body disease

Lin, Michael; Cantuti-Castelvetri, Ippolita; Zheng, Kangni; Jackson, Katie; Tan, Yong B.; Arzberger, Thomas; Lees, Andrew J.; Betensky, Rebecca A.; Beal, M. Flint; Simon, David K.

doi:10.1002/ana.23568

Cited by 114 publications

(87 citation statements)

References 22 publications

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“…Alternatively, the discordance between our findings and earlier reports could be explained by their use of PCR based assays, which can lead to erroneous misincorporation events, to quantify mutations. Consistent with this possibility is that the mutation frequencies we report here are ~10-fold lower than those reported in these studies, 5, 23 and are in closer agreement with previous studies in humans. 6 …”

Section: Discussionsupporting

confidence: 94%

“…23 This striking contrast points to an underlying difference in the etiologies of AD and PD and suggests that, unlike early PD, mitochondrially localized oxidative stress may not be an early contributor to AD. Alternatively, the discordance between our findings and earlier reports could be explained by their use of PCR based assays, which can lead to erroneous misincorporation events, to quantify mutations.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial DNA mutations increase in early stage Alzheimer disease and are inconsistent with oxidative damage

Hoekstra

Hipp

Montine

et al. 2016

Annals of Neurology

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Mitochondrial dysfunction and oxidative damage are commonly associated with early stage Alzheimer’s disease (AD). The accumulation of somatic mutations in mitochondrial DNA (mtDNA) has been hypothesized to be a driver of these phenotypes, but the detection of increased mutation loads has been difficult due to a lack of sensitive methods. We used an ultra-sensitive next-generation sequencing technique to measure the mutation load of the entire mitochondrial genome. Here, we report a significant increase in the mtDNA mutation frequency in the hippocampus of early-stage AD, with the cause of these mutations being consistent with replication errors and not oxidative damage.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA mutations increase in early stage Alzheimer disease and are inconsistent with oxidative damage

Hoekstra

Hipp

Montine

et al. 2016

Annals of Neurology

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“…MPTP also is of interest because it selectively damages dopaminergic neurons, and accidental human exposure to MPTP can cause clinical features similar to Parkinson’s disease (PD) (Langston et al, 1983; Langston 1996). 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).…”

Section: Introductionmentioning

confidence: 88%

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

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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.

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“…The underlying pathogenic mechanisms are not well understood, although a growing body of research suggests mitochondrial respiratory dysfunction and oxidative stress contribute to disease pathogenesis [62][63][64][65]. In some Parkinson's disease patients, mtDNA mutations have also been detected, specifically in the D-loop region and the MT-ND5 gene [65]. …”

Section: Oxphos Complex Imentioning

confidence: 99%

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

2016

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SynopsisMitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP . Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis.Key words: disease, mitochondria, protein complex assembly, protein interactions, supercomplex. MITOCHONDRIAL METABOLISMMitochondria occupy almost all human cell types and are involved in essential metabolic and cellular processes, including calcium and iron homoeostasis, apoptosis, innate immunity and haeme biosynthesis [1]. However, the primary function of mitochondria is the production of energy in the form of ATP [2][3][4]. ATP is the body's energy currency, playing vital roles in cell differentiation, growth and reproduction, thermogenesis and powering the contraction of muscles for movement [1]. In humans, ATP is produced by two different processes; through the breakdown of glucose or other sugars in Abbreviations: ACAD9, acyl-CoA dehydrogenase 9; BN-PAGE, blue native polyacrylamide gel electrophoresis; CACT, carnitine acylcarnitine translocase; CI, oxidative phosphorylation complex I (NADH: ubiquinone oxidoreductase, EC 1.6.5.3); CII, oxidative phosphorylation complex II (succinate: ubiquinone oxidoreductase, EC 1.3.5.1); CIII, oxidative phosphorylation complex III (ubiquinol: ferricytochrome c oxidoreductase, EC 1.10.2.2); CIV, oxidative phosphorylation complex IV (cytochrome c oxidase, EC 1.9.3.1); COPP , complex one phylogenetic profile; CPT1, carnitine O-palmitoyltransferase 1; CPT2, carnitine O-palmitoyltransferase 2; CV, OXPHOS complex V (FoF 1 -ATP synthetase, EC; 3.6.3.14); ECHS1, enoyl-CoA hydratase, short chain 1, mitochondrial; ECI1, enoyl-CoA delta isomerase, 1; ETF, electron transfer flavoprotein; ETFA, electron transfer flavoprotein alpha subunit; ETFB, electron transfer flavoprotein beta subunit; ETF-QO, electron transfer flavoprotein: ubiquinone oxidoreductase; FAD, flavin adenine dinucleotide; FADH 2 , reduced flavin adenine dinucleotide; FAO, fatty acid β-oxidation; H 2 O, water; HADH, hydroxyacyl-CoA dehydrogenase; KAT, 3-ketoacyl-CoA thiolase, mitochondrial; LCAD, long chain acyl-CoA dehydrogenase; LCEH, long chain enoyl-CoA hydra...

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Somatic mitochondrial DNA mutations in early parkinson and incidental lewy body disease

Cited by 114 publications

References 22 publications

Mitochondrial DNA mutations increase in early stage Alzheimer disease and are inconsistent with oxidative damage

Mitochondrial DNA mutations increase in early stage Alzheimer disease and are inconsistent with oxidative damage

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

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

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