Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3.

Recessive mutations in DNAJC3, an endoplasmic reticulum (ER)-resident BiP co-chaperone, have been identified in patients with multisystemic neurodegeneration and diabetes mellitus. To further unravel these pathomechanisms, we employed a non-biased proteomic approach and identified dysregulation of several key cellular pathways, suggesting a pathophysiological interplay of perturbed lipid metabolism, mitochondrial bioenergetics, ER-Golgi function, and amyloid-beta processing. Further functional investigations in fibroblasts of patients with DNAJC3 mutations detected cellular accumulation of lipids and an increased sensitivity to cholesterol stress, which led to activation of the unfolded protein response (UPR), alterations of the ER-Golgi machinery, and a defect of amyloid precursor protein. In line with the results of previous studies, we describe here alterations in mitochondrial morphology and function, as a major contributor to the DNAJC3 pathophysiology. Hence, we propose that the loss of DNAJC3 affects lipid/cholesterol homeostasis, leading to UPR activation, β-amyloid accumulation, and impairment of mitochondrial oxidative phosphorylation

Comparative In Vivo Effects of Hemoglobin-Based Oxygen Carriers (HBOC) with Varying Prooxidant and Physiological Reactivity.

A series of hemoglobin-based oxygen carrier candidates (HBOC), previously noted for their differences in prooxidative and physiological reactivity, were compared in terms of the negative effects displayed upon injection in Wistar rats. At the concentrations tested, antioxidant strategies based on albumin as well as based on rubrerythrin appear to offer observable physiological advantages

EPR spectra of Wistar rat venous blood (c.f. Materials and Methods) measured at 100K; the <i>g</i> values are indicated by arrows.

<p>EPR spectra of Wistar rat venous blood (c.f. Materials and Methods) measured at 100K; the <i>g</i> values are indicated by arrows.</p

Immunological and clotting parameters of Control and experimental groups.

<p>Values are expressed as mean ± SD.</p

Comparative <i>In Vivo</i> Effects of Hemoglobin-Based Oxygen Carriers (HBOC) with Varying Prooxidant and Physiological Reactivity

<div><p>A series of hemoglobin-based oxygen carrier candidates (HBOC), previously noted for their differences in prooxidative and physiological reactivity, were compared in terms of the negative effects displayed upon injection in Wistar rats. At the concentrations tested, antioxidant strategies based on albumin as well as based on rubrerythrin appear to offer observable physiological advantages.</p></div

Comparison of the iron deposits in liver, spleen and kidney in Control and experimental groups.

<p>The structures were scored for their intensities of iron deposition in the range of + (normal aspects of the analyzed structures) and ++++ (the most intensely stained areas). The absence of iron deposits was marked with–(negative).</p

Blood ion concentration of control and experimental groups (mean ± SEM).

<p>Blood ion concentration of control and experimental groups (mean ± SEM).</p

Renal function parameters of control and experimental groups.

<p>Values are expressed as mean ± SEM.</p

EPR data for blood collected after injection of animals (n = 6) with 200 μL HBOC candidate.

<p>Percentage changes relative to the control group are shown, for the concentrations of metHb (g~6), free radical (g~2) and transferrin (g~ 4.1) signals, respectively.</p

Transferrin, total proteins, and glucose in control and experimental groups.

<p>Values are expressed as mean ± SEM</p