Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.9.3.1 (cytochrome oxidase)
 8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amyloid-beta peptide accumulation in the brain is one of the main hallmarks of Alzheimer's disease. The amyloid aggregation process is associated with the generation of free radical species responsible for mitochondrial impairment and DNA damage that in turn activates poly(ADP-ribose)polymerase 1 (PARP-1). PARP-1 catalyzes the poly(ADP-ribosylation), a post-translational modification of proteins, cleaving the substrate NAD+ and transferring the ADP-ribose moieties to the enzyme itself or to an acceptor protein to form branched polymers of ADP-ribose. In this paper, we demonstrate that a mitochondrial dysfunction occurs in Alzheimer's transgenic mice TgCRND8, in SH-SY5Y treated with amyloid-beta and in 7PA2 cells. Moreover, PARP-1 activation contributes to the functional energetic decline affecting cytochrome oxidase IV protein levels, oxygen consumption rates, and membrane potential, resulting in cellular bioenergetic deficit. We also observed, for the first time, an increase of pyruvate kinase 2 expression, suggesting a modulation of the glycolytic pathway by PARP-1. PARP-1 inhibitors are able to restore both mitochondrial impairment and pyruvate kinase 2 expression. The overall data here presented indicate a pivotal role for this enzyme in the bioenergetic network of neuronal cells and open new perspectives for investigating molecular mechanisms underlying energy charge decline in Alzheimer's disease. In this scenario, PARP-1 inhibitors might represent a novel therapeutic intervention to rescue cellular energetic metabolism.
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PMID:Bioenergetic Impairment in Animal and Cellular Models of Alzheimer's Disease: PARP-1 Inhibition Rescues Metabolic Dysfunctions. 2756 5

Although childhood-onset obesity (CO) and adulthood-onset obesity (AO) are known to lead to distinctive clinical manifestations and disease risks, the fundamental differences between them are largely unclear. The aim of the current study is to investigate the fundamental differences between subcutaneous adipose tissue from CO and AO and to identify metabolic differences between abdominal (abSAT) and femoral subcutaneous adipose tissues (feSAT). Total and regional body composition was assessed using dual-energy x-ray absorptiometry (DXA) and computed tomography. Levels of acetyl-CoA, NAD+/NADH, acetyl-CoA network genes, mitochondrial complex abundance, H3 acetylation were determined in biopsied abSAT and feSAT. Serum leptin and adiponectin were measured. Our results showed that acetyl-CoA was higher in subcutaneous adipose tissue from subjects with AO compared with CO. Multiple linear regression revealed that ATP citrate lyase was the only main effect affecting the level of acetyl-CoA. Circulating leptin concentrations was higher in AO. The increased level of acetyl-CoA was strongly associated with histone H3 acetylation, LEP expression in adipose tissue, and circulating leptin in AO. NAD+/NADH was higher in CO; however, abundance of mitochondrial complexes, the complex II:complex V ratio, and the complex IV:complex V ratio were lower in CO, reflecting compromised mitochondrial function in subcutaneous adipose tissue from CO. Moreover, we identified differences in the level of acetyl-CoA and NAD+/NADH ratio between abSAT and feSAT, suggesting that these fat depots may possess different metabolic properties. The fundamental difference in the important metabolic intermediate acetyl-CoA between CO and AO may help us better understand the development of obesity and the pathogenesis of different obesity-related diseases in humans.
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PMID:Acetyl-CoA Regulation, OXPHOS Integrity and Leptin Levels Are Different in Females With Childhood vs Adulthood Onset of Obesity. 3280 57


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