Biomarkers for Detecting Mitochondrial Disorders

Finsterer, Josef; Zarrouk‐Mahjoub, Sinda

doi:10.3390/jcm7020016

Cited by 34 publications

(28 citation statements)

References 42 publications

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“…Creatine kinase is an enzyme highly expressed in tissues that rapidly consume energy such as skeletal muscle and brain, which are frequently affected in mitochondrial diseases. Creatine kinase is suggested as a potential biomarker to reflect mitochondrial dysfunction 36 , for which genetic and phenotypic link with mitochondria should provide novel biological insights. Patients affected with mitochondrial diseases often confer endocrine dysfunction including thyroid hormones 37 , whereas the biological link with a liver function-related trait is elusive.…”

Section: Resultsmentioning

confidence: 99%

Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population

et al. 2020

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The genetic landscape of mitochondrial DNA (mtDNA) has been elusive. By analyzing mtDNA using the whole genome sequence (WGS) of Japanese individuals (n = 1928), we identified 2023 mtDNA variants and high-resolution haplogroups. Frequency spectra of the haplogroups were population-specific and were heterogeneous among geographic regions within Japan. Application of machine learning methods could finely classify the subjects corresponding to the high-digit mtDNA sub-haplogroups. mtDNA had distinct genetic structures from that of nuclear DNA (nDNA), characterized by no distance-dependent linkage disequilibrium decay, sparse tagging of common variants, and the existence of common haplotypes spanning the entire mtDNA. We did not detect any evidence of mtDNA-nDNA (or mtDNA copy number-nDNA) genotype associations. Together with WGS-based mtDNA variant imputation, we conducted a phenome-wide association study of 147,437 Japanese individuals with 99 clinical phenotypes. We observed pleiotropy of mtDNA genetic risk on the five late-onset human complex traits including creatine kinase (P = 1.7 × 10 −12).

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Section: Resultsmentioning

confidence: 99%

Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population

et al. 2020

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“…Other potential biomarkers include growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21), which are newer mitochondrial biomarkers that possess a high specificity for MD [ 82 ]. They have yet to be studied in ASD patients.…”

Section: Summary Of the Literaturementioning

confidence: 99%

Clinical and Molecular Characteristics of Mitochondrial Dysfunction in Autism Spectrum Disorder

Rose

Niyazov

Rossignol³

et al. 2018

Mol Diagn Ther

186

148

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Autism spectrum disorder (ASD) affects ~ 2% of children in the United States. The etiology of ASD likely involves environmental factors triggering physiological abnormalities in genetically sensitive individuals. One of these major physiological abnormalities is mitochondrial dysfunction, which may affect a significant subset of children with ASD. Here we systematically review the literature on human studies of mitochondrial dysfunction related to ASD. Clinical aspects of mitochondrial dysfunction in ASD include unusual neurodevelopmental regression, especially if triggered by an inflammatory event, gastrointestinal symptoms, seizures, motor delays, fatigue and lethargy. Traditional biomarkers of mitochondrial disease are widely reported to be abnormal in ASD, but appear non-specific. Newer biomarkers include buccal cell enzymology, biomarkers of fatty acid metabolism, non-mitochondrial enzyme function, apoptosis markers and mitochondrial antibodies. Many genetic abnormalities are associated with mitochondrial dysfunction in ASD, including chromosomal abnormalities, mitochondrial DNA mutations and large-scale deletions, and mutations in both mitochondrial and non-mitochondrial nuclear genes. Mitochondrial dysfunction has been described in immune and buccal cells, fibroblasts, muscle and gastrointestinal tissue and the brains of individuals with ASD. Several environmental factors, including toxicants, microbiome metabolites and an oxidized microenvironment are shown to modulate mitochondrial function in ASD tissues. Investigations of treatments for mitochondrial dysfunction in ASD are promising but preliminary. The etiology of mitochondrial dysfunction and how to define it in ASD is currently unclear. However, preliminary evidence suggests that the mitochondria may be a fruitful target for treatment and prevention of ASD. Further research is needed to better understand the role of mitochondrial dysfunction in the pathophysiology of ASD.

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“…As indicated above, we hypothesized that such a signal could be either endocrine or metabolic in nature, or a combination of both. Endocrine signals of metabolicspecifically mitochondrial stress are well established in other organisms, such as FGF21 or GDF15 in mammals [39]. Although both of these growth-factor superfamilies have representatives in insects, neither has a clear orthologue in Drosophila.…”

Section: Discussionmentioning

confidence: 99%

“…Candidates for a metabolic signal of mitochondrial dysfunction were already suggested by the previous observation of elevated pyruvate and lactate levels in tko 25t larvae [7], and the fact that their addition to the culture medium phenocopied the effects of highsugar on tko 25t . Serum lactate is already considered a key biomarker for diagnosing OXPHOS disorders in humans [39], whilst pyruvate has been identified as a crucial regulator of stemness and growth in mammalian cells [51]. In flies, the enzyme that interconverts lactate and pyruvate, lactate dehydrogenase (Ldh, or ImpL3) has previously been implicated as a target of growth signalling by the estrogen-related receptor [52].…”

Section: Tissue-specificity Of the Bang-sensitive Phenotypementioning

confidence: 99%

Mitochondrial dysfunction generates a growth-restraining signal linked to pyruvate inDrosophilalarvae

George

Tuomela

Kemppainen

et al. 2019

Fly

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The Drosophila bang-sensitive mutant tko 25t , manifesting a global deficiency in oxidative phosphorylation due to a mitochondrial protein synthesis defect, exhibits a pronounced delay in larval development. We previously identified a number of metabolic abnormalities in tko 25t larvae, including elevated pyruvate and lactate, and found the larval gut to be a crucial tissue for the regulation of larval growth in the mutant. Here we established that expression of wild-type tko in any of several other tissues of tko 25t also partially alleviates developmental delay. The effects appeared to be additive, whilst knockdown of tko in a variety of specific tissues phenocopied tko 25t , producing developmental delay and bang-sensitivity. These findings imply the existence of a systemic signal regulating growth in response to mitochondrial dysfunction. Drugs and RNAi-targeted on pyruvate metabolism interacted with tko 25t in ways that implicated pyruvate or one of its metabolic derivatives in playing a central role in generating such a signal. RNA-seq revealed that dietary pyruvate-induced changes in transcript representation were mostly non-coherent with those produced by tko 25t or high-sugar, consistent with the idea that growth regulation operates primarily at the translational and/or metabolic level. ARTICLE HISTORY

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Biomarkers for Detecting Mitochondrial Disorders

Cited by 34 publications

References 42 publications

Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population

Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population

Clinical and Molecular Characteristics of Mitochondrial Dysfunction in Autism Spectrum Disorder

Mitochondrial dysfunction generates a growth-restraining signal linked to pyruvate inDrosophilalarvae

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