Eukaryotic histone H3-H4 tetramers contain a putative copper (Cu2+) binding site at the H3-H3′ dimerization interface with unknown function. The coincident emergence of eukaryotes with global oxygenation, which challenged cellular copper utilization, raised the possibility that histones may function in cellular copper homeostasis. We report that the recombinant Xenopus laevis H3-H4 tetramer is an oxidoreductase enzyme that binds Cu2+ and catalyzes its reduction to Cu1+ in vitro. Loss- and gain-of-function mutations of the putative active site residues correspondingly altered copper binding and the enzymatic activity, as well as intracellular Cu1+ abundance and copper-dependent mitochondrial respiration and Sod1 function in the yeast Saccharomyces cerevisiae. The histone H3-H4 tetramer, therefore, has a role other than chromatin compaction or epigenetic regulation and generates biousable Cu1+ ions in eukaryotes.

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This study examined the effects of 6 weeks of moderate- (MD) and high-intensity endurance training (HD) and resistance training (RD) on the vasorelaxation responsiveness of the aorta, iliac, and femoral vessels in type 1 diabetic (D) rats. Vasorelaxation to acetylcholine was modeled as a mono-exponential function. A potential mediator of vasorelaxation, endothelial nitric oxide synthase (e-NOS) was determined by Western blots. Vessel lumen-to-wall ratios were calculated from H&E stains. The vasorelaxation time-constant (τ) (s) was smaller in control (C) (7.2±3.7) compared to D (9.1±4.4) and it was smaller in HD (5.4±1.5) compared to C, D, RD (8.3±3.7) and MD (8.7±3.8) (p<0.05). The rate of vasorelaxation (%·s−1) was larger in HD (2.7±1.2) compared to C (2.0±1.2), D (2.0±1.5), RD (2.0±1.0), and MD (2.0±1.2) (p<0.05). τ vasorelaxation was smaller in the femoral (6.9±3.7) and iliac (6.9±4.7) than the aorta (9.0±5.0) (p<0.05). The rate of vasorelaxation was progressively larger from the femoral (3.1±1.4) to the iliac (2.0±0.9) and to the aorta (1.3±0.5) (p<0.05). e-NOS content (% of positive control) was greater in HD (104±90) compared to C (71±64), D (85±65), RD (69±43), and MD (76±44) (p<0.05). e-NOS normalized to lumen-to-wall ratio (%·mm−1) was larger in the femoral (11.7±11.1) compared to the aorta (3.2±1.9) (p<0.05). Although vasorelaxation responses were vessel-specific, high-intensity endurance training was the most effective exercise modality in restoring the diabetes-related loss of vascular responsiveness. Changes in the vasoresponsiveness seem to be endothelium-dependent as evidenced by the greater e-NOS content in HD and the greater normalized e-NOS content in the smaller vessels.

The endoplasmic reticulum (ER)-mitochondria encounter structure (ERMES) is a protein complex that physically tethers the two organelles to each other and creates the physical basis for communication between them. ERMES functions in lipid exchange between the ER and mitochondria, protein import into mitochondria, and maintenance of mitochondrial morphology and genome. Here, we report that ERMES is also required for iron homeostasis. Loss of ERMES components activates an Aft1-dependent iron deficiency response even in iron-replete conditions, leading to accumulation of excess iron inside the cell. This function is independent of known ERMES roles in calcium regulation, phospholipid biosynthesis, or effects on mitochondrial morphology. A mutation in the vacuolar protein sorting 13 () gene that rescues the glycolytic phenotype of ERMES mutants suppresses the iron deficiency response and iron accumulation. Our findings reveal that proper communication between the ER and mitochondria is required for appropriate maintenance of cellular iron levels.

The rate of adjustment of endothelium-dependent vasorelaxation was examined in the aorta, iliac and femoral arteries of eight control and eight diabetic rats with and without supplementation with vitamin C. Vessels were constricted using 10(-5) M phenylephrine (PE) and relaxed with 10(-4) M acetylcholine (ACh condition) or 10(-4) M ACh plus 10(-4) M vitamin C (ACh + vitamin C condition) in a myography system. Vasorelaxation was modelled as a mono-exponential function using a non-linear regression analysis. The adjustment (τ) of vasorelaxation was faster in control (6.6 ± 3.2 s) compared to diabetic rats (8.4 ± 3.4 s) (p < 0.05). The time-to-steady-state tended to be shorter in control (32.0 ± 13.9 s) compared to diabetic rats (38.0 ± 15.0 s) (p = 0.1). ACh + vitamin C did not speed the vasorelaxation response. The τ for vasorelaxation was shorter in the femoral (6.5 ± 2.7 s) and iliac (6.8 ± 2.5 s) compared to the aorta (9.2 ± 4.2 s) (p < 0.05). The rate of vasorelaxation was greater in the femoral (3.2 ± 1.4%·s(-1)) compared to the iliac (2.0 ± 1.0%·s(-1)) and aorta (1.1 ± 0.4%·s(-1)) in both groups and in the iliac compared to the aorta (p < 0.05) in the control group. In conclusion, the vasorelaxation response was vessel specific with a slower rate of adjustment in diabetic compared to control animals.