Novel Metabolic Abnormalities in the Tricarboxylic Acid Cycle in Peripheral Cells From Huntington’s Disease Patients

Naseri, Nima; Bonica, Joseph; Xu, Hui; Park, Larry C.; Arjomand, Jamshid; Chen, Zhengming; Gibson, Gary E.

doi:10.1371/journal.pone.0160384

Cited by 23 publications

(13 citation statements)

References 43 publications

(54 reference statements)

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“…Indeed, this assumption is supported by decreased Aco2 activity of PBMC in PreHD carriers as well as HD patients in our study. Our results are in accordance with the previous repot that in the presence of oxidative stressors, Aco2 activity in lymphoblasts of HD decreased significantly compared with the controls [ 41 ]. The decreased Aco2 activity without changes in Aco2 protein level in PBMC of PreHD carriers also implicates that inactivation of Aco2 precedes protein degradation in HD.…”

Section: Discussionsupporting

confidence: 94%

Altered Aconitase 2 Activity in Huntington’s Disease Peripheral Blood Cells and Mouse Model Striatum

Chen

Chang

2017

IJMS

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Huntington’s disease (HD) is caused by an unstable cytosine adenine guanine (CAG) trinucleotide repeat expansion encoding a polyglutamine tract in the huntingtin protein. Previously, we identified several up- and down-regulated protein molecules in the striatum of the Hdh(CAG)150 knock-in mice at 16 months of age, a mouse model which is modeling the early human HD stage. Among those molecules, aconitase 2 (Aco2) located in the mitochondrial matrix is involved in the energy generation and susceptible to increased oxidative stress that would lead to inactivation of Aco2 activity. In this study, we demonstrate decreased Aco2 protein level and activity in the brain of both Hdh(CAG)150 and R6/2 mice. Aco2 activity was decreased in striatum of Hdh(CAG)150 mice at 16 months of age as well as R6/2 mice at 7 to 13 weeks of age. Aco2 activity in the striatum of R6/2 mice could be restored by the anti-oxidant, N-acetyl-l-cysteine, supporting that decreased Aco2 activity in HD is probably caused by increased oxidative damage. Decreased Aco2 activity was further found in the peripheral blood mononuclear cells (PBMC) of both HD patients and pre-symptomatic HD mutation (PreHD) carriers, while the decreased Aco2 protein level of PBMC was only present in HD patients. Aco2 activity correlated significantly with motor score, independence scale, and functional capacity of the Unified Huntington’s Disease Rating Scale as well as disease duration. Our study provides a potential biomarker to assess the disease status of HD patients and PreHD carriers.

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Section: Discussionsupporting

confidence: 94%

Altered Aconitase 2 Activity in Huntington’s Disease Peripheral Blood Cells and Mouse Model Striatum

Chen

Chang

2017

IJMS

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“…The Krebs cycle has a central role in liver metabolism, connecting hepatic fatty acid and glucose-related pathways. Abnormal cellular [20] and circulating [21] Krebs cycle intermediates are closely associated with mitochondrial dysfunction as was demonstrated in numerous studies [22][23][24][25]. Given the decreased activity in respiratory chain complexes in NAFLD [4], perturbations in cellular concentrations of Krebs cycle intermediates are expected.…”

Section: Resultsmentioning

confidence: 99%

Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease

Sandlers

Shah

Pearce

et al. 2020

JCM

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Nonalcoholic liver disease (NAFLD) is manifested with a wide spectrum of clinical symptoms and is closely associated with the metabolic syndrome, inflammation, and mitochondrial dysfunction. Although the mechanism of mitochondrial dysfunction in NAFLD is still not fully elucidated, multiple studies have demonstrated evidence of molecular, biochemical, and biophysical mitochondrial abnormalities in NAFLD. Given the association between NAFLD and mitochondrial dysfunction, the aim of this study is to analyze circulating levels of Krebs cycle intermediates in a cohort of NAFLD-affected individuals and matching healthy controls and to correlate our findings with the liver function metrics. Standard serum biochemistry and Krebs cycle intermediates were analyzed in NAFLD (n = 22) and matched control (n = 67) cohorts. Circulating levels of isocitrate and citrate were significantly (p < 0.05) elevated in the NAFLD cohort of patients. The area under the curve (AUROC) for these two metabolites exhibited a moderate clinical utility. Correlations between plasma Krebs cycle intermediates and standard clinical plasma metrics were explored by Pearson’s correlation coefficient. The data obtained for plasma Krebs cycle intermediates suggest pathophysiological insights that link mitochondrial dysfunction with NAFLD. Our findings reveal that plasma isocitrate and citrate can discriminate between normal and NAFLD cohorts and can be utilized as noninvasive markers of mitochondrial dysfunction in NAFLD. Future studies with large populations at different NAFLD stages are warranted.

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“…Later it was shown that patients with HD have severe defects of CII in caudate nucleus [64], which can mediate striatal cell death and neurodegeneration mimicking the development of HD [65]. On the other hand, Naseri et al recently measured an elevated SDH activity in HD patient lymphoblasts [66], pointing to a possible compartment-specific CII regulation.…”

Section: In Diseasementioning

confidence: 99%

Mitochondrial complex II and reactive oxygen species in disease and therapy

et al. 2020

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Increasing evidence points to the respiratory Complex II (CII) as a source and modulator of reactive oxygen species (ROS). Both functional loss of CII as well as its pharmacological inhibition can lead to ROS generation in cells, with a relevant impact on the development of pathophysiological conditions, i.e. cancer and neurodegenerative diseases. While the basic framework of CII involvement in ROS production has been defined, the fine details still await clarification. It is important to resolve these aspects to fully understand the role of CII in pathology and to explore its therapeutic potential in cancer and other diseases.

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Novel Metabolic Abnormalities in the Tricarboxylic Acid Cycle in Peripheral Cells From Huntington’s Disease Patients

Cited by 23 publications

References 43 publications

Altered Aconitase 2 Activity in Huntington’s Disease Peripheral Blood Cells and Mouse Model Striatum

Altered Aconitase 2 Activity in Huntington’s Disease Peripheral Blood Cells and Mouse Model Striatum

Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease

Mitochondrial complex II and reactive oxygen species in disease and therapy

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