Dataset Information

Ketogenic treatment reduces the percentage of a LHON heteroplasmic mutation and increases mtDNA amount of a LHON homoplasmic mutation.

ABSTRACT:

Background

The vision loss in Leber hereditary optic neuropathy patients is due to mitochondrial DNA mutations. No treatment has shown a clear-cut benefit on a clinically meaningful end-point. However, clinical evidences suggest two therapeutic approaches: the reduction of the mutation load in heteroplasmic patients or the elevation of mitochondrial DNA amount in homoplasmic patients.

Results

Here we show that ketogenic treatment, in cybrid cell lines, reduces the percentage of the m.13094 T > C heteroplasmic mutation and also increases the mitochondrial DNA levels of the m.11778G > A mitochondrial genotype.

Conclusions

These results suggest that ketogenic diet could be a therapeutic strategy for Leber hereditary optic neuropathy.

SUBMITTER: Emperador S

PROVIDER: S-EPMC6588889 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Ketogenic treatment reduces the percentage of a LHON heteroplasmic mutation and increases mtDNA amount of a LHON homoplasmic mutation.

Emperador Sonia S López-Gallardo Ester E Hernández-Ainsa Carmen C Habbane Mouna M Montoya Julio J Bayona-Bafaluy M Pilar MP Ruiz-Pesini Eduardo E

Orphanet journal of rare diseases 20190621 1

<h4>Background</h4>The vision loss in Leber hereditary optic neuropathy patients is due to mitochondrial DNA mutations. No treatment has shown a clear-cut benefit on a clinically meaningful end-point. However, clinical evidences suggest two therapeutic approaches: the reduction of the mutation load in heteroplasmic patients or the elevation of mitochondrial DNA amount in homoplasmic patients.<h4>Results</h4>Here we show that ketogenic treatment, in cybrid cell lines, reduces the percentage of th ...[more]

PMID: 31226990

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Project description:BackgroundSporadic Parkinson's disease (sPD) is a nervous system-wide disease that presents with a bradykinetic movement disorder and is frequently complicated by depression and cognitive impairment. sPD likely has multiple interacting causes that include increased oxidative stress damage to mitochondrial components and reduced mitochondrial bioenergetic capacity. We analyzed mitochondria from postmortem sPD and CTL brains for evidence of oxidative damage to mitochondrial DNA (mtDNA), heteroplasmic mtDNA point mutations and levels of electron transport chain proteins. We sought to determine if sPD brains possess any mtDNA genotype-respiratory phenotype relationships.ResultsTreatment of sPD brain mtDNA with the mitochondrial base-excision repair enzyme 8-oxyguanosine glycosylase-1 (hOGG1) inhibited, in an age-dependent manner, qPCR amplification of overlapping ~2 kbase products; amplification of CTL brain mtDNA showed moderate sensitivity to hOGG1 not dependent on donor age. hOGG1 mRNA expression was not different between sPD and CTL brains. Heteroplasmy analysis of brain mtDNA using Surveyor nuclease(R) showed asymmetric distributions and levels of heteroplasmic mutations across mtDNA but no patterns that statistically distinguished sPD from CTL. sPD brain mitochondria displayed reductions of nine respirasome proteins (respiratory complexes I-V). Reduced levels of sPD brain mitochondrial complex II, III and V, but not complex I or IV proteins, correlated closely with rates of NADH-driven electron flow. mtDNA levels and PGC-1alpha expression did not differ between sPD and CTL brains.ConclusionPD brain mitochondria have reduced mitochondrial respiratory protein levels in complexes I-V, implying a generalized defect in respirasome assembly. These deficiencies do not appear to arise from altered point mutational burden in mtDNA or reduction of nuclear signaling for mitochondrial biogenesis, implying downstream etiologies. The origin of age-related increases in distribution of oxidative mtDNA damage in sPD but not CTL brains is not clear, tracks with but does not determine the sPD phenotype, and may indicate a unique consequence of aging present in sPD that could contribute to mtDNA deletion generation in addition to mtDNA replication, transcription and sequencing errors. sPD frontal cortex experiences a generalized bioenergetic deficiency above and beyond aging that could contribute to mood disorders and cognitive impairments.

Dataset Information

Ketogenic treatment reduces the percentage of a LHON heteroplasmic mutation and increases mtDNA amount of a LHON homoplasmic mutation.

Background

Results

Conclusions

Publications

Ketogenic treatment reduces the percentage of a LHON heteroplasmic mutation and increases mtDNA amount of a LHON homoplasmic mutation.

Similar Datasets

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