scholarly journals Mitochondrial Dysfunction in Astrocytes: A Role in Parkinson’s Disease?

2021 ◽  
Vol 8 ◽  
Author(s):  
Collin M. Bantle ◽  
Warren D. Hirst ◽  
Andreas Weihofen ◽  
Evgeny Shlevkov
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Fatty Acid ◽  
Mitochondrial Dysfunction ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Glutamate Metabolism ◽  
Cell Type ◽  
Therapeutic Development ◽  
The Brain

Mitochondrial dysfunction is a hallmark of Parkinson’s disease (PD). Astrocytes are the most abundant glial cell type in the brain and are thought to play a pivotal role in the progression of PD. Emerging evidence suggests that many astrocytic functions, including glutamate metabolism, Ca2+ signaling, fatty acid metabolism, antioxidant production, and inflammation are dependent on healthy mitochondria. Here, we review how mitochondrial dysfunction impacts astrocytes, highliting translational gaps and opening new questions for therapeutic development.

scholarly journals Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study

PLoS Medicine ◽  
2017 ◽  
Vol 14 (3) ◽  
pp. e1002266 ◽  
Author(s):  
Stuart G. Snowden ◽  
Amera A. Ebshiana ◽  
Abdul Hye ◽  
Yang An ◽  
Olga Pletnikova ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Alzheimer Disease ◽  
Cognitive Performance ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
The Brain ◽  
Metabolomic Study

scholarly journals CROT (Carnitine O-Octanoyltransferase) Is a Novel Contributing Factor in Vascular Calcification via Promoting Fatty Acid Metabolism and Mitochondrial Dysfunction

2020 ◽  
Author(s):  
Takehito Okui ◽  
Masaya Iwashita ◽  
Maximillian A. Rogers ◽  
Arda Halu ◽  
Samantha K. Atkins ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Carotid Artery ◽  
Mitochondrial Dysfunction ◽  
Vascular Calcification ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Plasma Cholesterol ◽  
Human Coronary Artery ◽  
Carotid Artery Calcification ◽  
Collagen Secretion

Objective: Vascular calcification is a critical pathology associated with increased cardiovascular event risk, but there are no Food and Drug Administration-approved anticalcific therapies. We hypothesized and validated that an unbiased screening approach would identify novel mediators of human vascular calcification. Approach and Results: We performed an unbiased quantitative proteomics and pathway network analysis that identified increased CROT (carnitine O-octanoyltransferase) in calcifying primary human coronary artery smooth muscle cells (SMCs). Additionally, human carotid artery atherosclerotic plaques contained increased immunoreactive CROT near calcified regions. CROT siRNA reduced fibrocalcific response in calcifying SMCs. In agreement, histidine 327 to alanine point mutation inactivated human CROT fatty acid metabolism enzymatic activity and suppressed SMC calcification. CROT siRNA suppressed type 1 collagen secretion, and restored mitochondrial proteome alterations, and suppressed mitochondrial fragmentation in calcifying SMCs. Lipidomics analysis of SMCs incubated with CROT siRNA revealed increased eicosapentaenoic acid, a vascular calcification inhibitor. CRISPR/Cas9-mediated Crot deficiency in LDL (low-density lipoprotein) receptor-deficient mice reduced aortic and carotid artery calcification without altering bone density or liver and plasma cholesterol and triglyceride concentrations. Conclusions: CROT is a novel contributing factor in vascular calcification via promoting fatty acid metabolism and mitochondrial dysfunction, as such CROT inhibition has strong potential as an antifibrocalcific therapy.

Effect of Enoxacin, Felbinac, and Sparfloxacin on Fatty Acid Metabolism and Glucose Concentrations in Rat Tissues

2011 ◽  
Vol 30 (3) ◽  
pp. 367-376 ◽  
Author(s):  
Fumiyo Kasuya ◽  
Yasushi Miwa ◽  
Maya Kazumi ◽  
Hiroyuki Inoue ◽  
Hiroyuki Ohta
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Rat Tissues ◽  
Antimicrobial Drugs ◽  
Glucose Levels ◽  
Chain Acyl ◽  
The Brain ◽  
Long Chain ◽  
Increased Susceptibility

Multiple changes in metabolic levels could be useful for understanding physiological toxicity. To explore further risk factors for the convulsions induced by the interaction of nonsteroidal anti-inflammatory and new quinolone antimicrobial drugs, the effect of sparfloxacin, enoxacin, and felbinac on fatty acid metabolism and glucose concentrations in the liver, brain, and blood of rats was investigated. The levels of long-chain acyl-CoAs (C18:1 and C20:4) in the liver and brain were decreased at the onset of convulsions induced by the coadministration of enoxacin with felbinac. Then, glucose concentrations in the liver and blood were decreased, whereas they were increased in a dose-dependant manner in the brain. However, the formation of acyl-CoAs and glucose levels in the liver, brain, and blood was not significantly influenced by enoxacin, felbinac, and sparfloxacin alone, respectively. The disturbance of both fatty acid metabolism and glucose levels might be associated with the increased susceptibility to convulsions, which may contribute to further understanding of the toxic effects associated with these drugs.

scholarly journals Blood Lactate Functions as a Signal for Enhancing Fatty Acid Metabolism during Exercise via TGF-^|^beta; in the Brain

2012 ◽  
Vol 58 (2) ◽  
pp. 88-95 ◽  
Author(s):  
Hiroyuki YAMADA ◽  
Yoko IWAKI ◽  
Ryo KITAOKA ◽  
Mina FUJITANI ◽  
Tetsuro SHIBAKUSA ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Blood Lactate ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Tgf Beta ◽  
The Brain

scholarly journals ABCA7 Regulates Brain Fatty Acid Metabolism During LPS-Induced Acute Inflammation

2021 ◽  
Vol 15 ◽  
Author(s):  
Tomonori Aikawa ◽  
Yingxue Ren ◽  
Marie-Louise Holm ◽  
Yan W. Asmann ◽  
Amer Alam ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Premature Termination Codon ◽  
Susceptibility Loci ◽  
Loss Of Function ◽  
Transporter Family ◽  
Increased Risk ◽  
Metabolite Content ◽  
The Brain

The ATP binding cassette subfamily A member 7 (ABCA7) gene is one of the significant susceptibility loci for Alzheimer’s disease (AD). Furthermore, ABCA7 loss of function variants resulting from premature termination codon in the gene are associated with increased risk for AD. ABCA7 belongs to the ABC transporter family, which mediates the transport of diverse metabolites across the cell membrane. ABCA7 is also involved in modulating immune responses. Because the immune system and lipid metabolism causatively engage in the pathogenesis of AD, we investigated how ABCA7 haplodeficiency modulates the metabolic profile in mouse brains during acute immune response using a metabolomics approach through LC/Q-TOF-MS. Peripheral lipopolysaccharide (LPS) stimulation substantially influenced the metabolite content in the cortex, however, the effect on metabolic profiles in Abca7 heterozygous knockout mice (Abca7±) was modest compared to that in the control wild-type mice. Weighted gene co-expression network analysis (WGCNA) of the metabolomics dataset identified two modules influenced by LPS administration and ABCA7 haplodeficiency, in which glycerophospholipid metabolism, linoleic acid metabolism, and α-linolenic acid metabolism were identified as major pathways. Consistent with these findings, we also found that LPS stimulation increased the brain levels of eicosapentaenoic acid, oleic acid, and palmitic acid in Abca7± mice, but not control mice. Together, our results indicate that ABCA7 is involved in the crosstalk between fatty acid metabolism and inflammation in the brain, and disturbances in these pathways may contribute to the risk for AD.

scholarly journals 064 Parkinson’s disease and the gastrointestinal microbiome: clinicopathological correlations and controversies

2019 ◽  
Vol 90 (e7) ◽  
pp. A21.1-A21
Author(s):  
Michal Lubomski ◽  
Ai Huey Tan ◽  
Shen-Yang Lim ◽  
Andrew Holmes ◽  
Ryan L Davis ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Short Chain Fatty Acid ◽  
Acid Metabolism ◽  
Intestinal Inflammation ◽  
Control Groups ◽  
Cross Sectional ◽  
Gastrointestinal Microbiome ◽  
Healthy Control ◽  
The Brain

IntroductionThere has been a recent surge in interest around the gastrointestinal microbiome (GM) and its association with Parkinson’s disease (PD). The GM mediates interactions between the brain and the gut via the ‘microbiota-gut-brain-axis’. Compelling studies suggest that a shift in GM composition may play an important role in the pathogenesis and progression of PD.MethodsWe conducted a literature review exploring the pathological association between the GM, α-synuclein spread and intestinal inflammation in PD. We also summarised patterns and correlations of gut microflora seen in clinical studies of the GM in PD.ResultsTo date 14 mainly cross-sectional studies from 7 countries have reported GM alterations in PD. All studies described significant alterations between PD and healthy control groups across multiple bacterial families, genera and species. Several studies suggested that putative ‘pro-inflammatory’ bacteria were significantly more abundant, while putative beneficial bacteria were less abundant in PD. Various complex microbiota-gut-brain-axis interactions have been proposed due to alterations in the GM, inferred by changes in gut mucosal integrity and permeability, short-chain-fatty-acid metabolism, oxidative stress and inflammation.ConclusionsAcross the recent GM studies in PD, alterations in bacterial taxa have been repeatedly associated with various clinicopathological features, endorsing a plausible biological link between the GM and PD. Mechanisms involved in the pathogenesis of PD due to GM changes are complex and require ongoing study.

scholarly journals Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 711
Author(s):  
Kristina Wardelmann ◽  
Michaela Rath ◽  
José Pedro Castro ◽  
Sabine Blümel ◽  
Mareike Schell ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Mitochondrial Dysfunction ◽  
Fatty Acid Metabolism ◽  
Mitochondrial Function ◽  
Insulin Signaling ◽  
Acid Metabolism ◽  
Early Event ◽  
Hypothalamic Function

Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance.

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