Coenzyme A (CoA) and acetyl-coenzyme A (acetyl-CoA) play essential roles in cell energy metabolism. Dysregulation of the biosynthesis and functioning of both compounds may contribute to various pathological conditions. We describe here a simple and sensitive HPLC-UV based method for simultaneous determination of CoA and acetyl-CoA in a variety of biological samples, including cells in culture, mouse cortex, and rat plasma, liver, kidney, and brain tissues. The limits of detection for CoA and acetyl-CoA are >10-fold lower than those obtained by previously described HPLC procedures, with coefficients of variation <1% for standard solutions, and 1–3% for deproteinized biological samples. Recovery is 95–97% for liver extracts spiked with Co-A and acetyl-CoA. Many factors may influence the tissue concentrations of CoA and acetyl-CoA (e.g., age, fed, or fasted state). Nevertheless, the values obtained by the present HPLC method for the concentration of CoA and acetyl-CoA in selected rodent tissues are in reasonable agreement with literature values. The concentrations of CoA and acetyl-CoA were found to be very low in rat plasma, but easily measurable by the present HPLC method. The method should be useful for studying cellular energy metabolism under normal and pathological conditions, and during targeted drug therapy treatment.

Mitochondrial DNA (mtDNA) mutator mice express a mutated form of mtDNA polymerase gamma (PolgA) that results an accelerated accumulation of somatic mtDNA mutations in association with a premature aging phenotype. An exploratory metabolomic analysis of cortical metabolites in sedentary and exercised mtDNA mutator mice and wild-type (WT) littermate controls at 9–10 months of age was performed. Pathway analysis revealed deficits in the neurotransmitters acetylcholine, glutamate and aspartate that were ameliorated by exercise. Nicotinamide adenine dinucleotide (NAD+) depletion and evidence of increased Poly [ADP-ribose] polymerase 1 (PARP-1) activity were apparent in sedentary mtDNA mutator mouse cortex, along with deficits in carnitine metabolites and an upregulated antioxidant response that largely normalized with exercise. These data highlight specific pathways that are altered in the brain in association with an accelerated age-related accumulation of somatic mtDNA mutations. These results may have relevance to age-related neurodegenerative diseases associated with mitochondrial dysfunction, such as Alzheimer’s disease and Parkinson’s disease, and provide insights into potential mechanisms of beneficial effects of exercise on brain function.

Introduction Improved methods are needed to detect and quantify age‐related muscle change. In this study we assessed the electrical properties of muscle impacted by acquired mitochondrial DNA mutations via the PolG mouse, which exhibits typical age‐associated features, and the impact of a potential therapy, nicotinamide mononucleotide (NMN). Methods The gastrocnemii of 24 PolG and 30 wild‐type (WT) mice (8 PolG and 17 WT treated with NMN) were studied in an electrical impedance‐measuring cell. Conductivity and relative permittivity were determined from the impedance data. Myofiber cross‐sectional area (CSA) was quantified histologically. Results Untreated PolG mice demonstrated alterations in several impedance features, including 50‐kHz relative permittivity and center frequency. A potential effect of NMN was also observed in these parameters in PolG but not WT animals. Impedance values correlated with myofiber CSA. Discussion Electrical impedance is sensitive to myofiber features considered characteristic of aging and to the impact of a potential therapy.

Pioglitazone, an oral hypoglycemic agent, recently failed to show promise as a disease-modifying agent in a 44-week phase 2 placebo-controlled study in 210 Parkinson’s disease (PD) subjects. We analyzed peripheral biomarkers, including leukocyte PGC-1α and target gene expression, plasma interleukin 6 (IL-6) as a marker of inflammation, and urine 8-hydroxydeoxyguanosine (8OHdG) as a marker of oxidative DNA damage. Baseline or changes from baseline in biomarker levels were not associated with the rate of progression of PD. Pioglitazone did not significantly alter biomarker levels. Other agents that more effectively target these mechanisms remain of potential interest as disease modifying therapies in PD.

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We have investigated the role of extracellular Heat shock protein 90 alpha (eHsp90α) in conferring protection of neuronal cells against fibrillary amyloid-beta (f-Aβ1-42) toxicity mediated by microglial cells. The formation of f-Aβ1-42 plaques leads to neurotoxic inflammation, a critical pathological feature of Alzheimer's Disease. We observed increased uptake and clearance of internalized f-Aβ1-42 by microglial cells treated with eHsp90α, an effect associated with activation of NRF2 (NF-E2-related factor 2) - mediated autophagy. eHsp90α thus mitigated the neuronal toxicity of f-Aβ1-42-activated microglia. In addition, eHsp90α facilitated f-Aβ1-42 engulfment by microglial cells in vitro. In summary, eHsp90α triggers NRF2-mediated autophagy in microglia and thus protects against the neurotoxic effects of f-Aβ1-42.