The Effects of Heat Stress on the Immune Function and Morphological Structure of Avian Gut-associated Lymphoid Tissues

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Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases

Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model “Mitomouse” (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial

Crucial role of membrane potential in heat stress-induced overproduction of reactive oxygen species in avian skeletal muscle mitochondria.

Heat stress is an environmental factor that causes oxidative stress. We found previously that acute heat stress stimulates the production of reactive oxygen species (ROS) in the skeletal muscle mitochondria of birds, and that this was accompanied by an increase of the mitochondrial membrane potential (ΔΨ) due to increased substrate oxidation by the electron transport chain. We also showed that avian uncoupling protein (avUCP) expression is decreased by the heat exposure. The present study clarifies whether ΔΨ is a major determinant of the overproduction of ROS due to acute heat stress, and if the decrease in avUCP expression is responsible for the elevation in ΔΨ. Control (24°C) and acute heat-stressed (34°C for 12 h) birds exhibited increased succinate-driven mitochondrial ROS production as indicated by an elevation of ΔΨ, with this increase being significantly higher in the heat-stressed group compared with the control group. In glutamate/malate-energized mitochondria, no difference in the ROS production between the groups was observed, though the mitochondrial ΔΨ was significantly higher in the heat-stressed groups compared with the control group. Furthermore, mitochondria energized with either succinate/glutamate or succinate/malate showed increased ROS production and ΔΨ in the heat-stressed group compared with mitochondria from the control group. These results suggest that succinate oxidation could play an important role in the heat stress-induced overproduction of mitochondrial ROS in skeletal muscle. In agreement with the notion of a decrease in avUCP expression in response to heat stress, proton leak, which was likely mediated by UCP (that part which is GDP-inhibited and arachidonic acid-sensitive), was reduced in the heat-exposed group. We suggest that the acute heat stress-induced overproduction of mitochondrial ROS may depend on ΔΨ, which may in turn result not only from increased substrate oxidation but also from a decrease in the mitochondrial avUCP content

Mechanisms underlying the Effects of Heat Stress on Intestinal Integrity, Inflammation, and Microbiota in Chickens

Poultry meat and egg production benefits from a smaller carbon footprint, as well as feed and water consumption, per unit of product, than other protein sources. Therefore, maintaining a sustainable production of poultry meat is important to meet the increasing global demand for this staple. Heat stress experienced during the summer season or in tropical/subtropical areas negatively affects the productivity and health of chickens. Crucially, its impact is predicted to grow with the acceleration of global warming. Heat stress affects the physiology, metabolism, and immune response of chickens, causing electrolyte imbalance, oxidative stress, endocrine disorders, inflammation, and immunosuppression. These changes do not occur independently, pointing to a systemic mechanism. Recently, intestinal homeostasis has been identified as an important contributor to nutrient absorption and the progression of systemic inflammation. Its mechanism of action is thought to involve neuroendocrine signaling, antioxidant response, the presence of oxidants in the diet, and microbiota composition. The present review focuses on the effect of heat stress on intestinal dysfunction in chickens and the underlying causative factors. Understanding these mechanisms will direct the design of strategies to mitigate the negative effect of heat stress, while benefiting both animal health and sustainable poultry production

Differences in Breast Muscle Mitochondrial Respiratory Capacity, Reactive Oxygen Species Generation, and Complex Characteristics between 7-week-old Meat- and Laying-type Chickens

The skeletal muscle growth rate is a major feature differentiating meat- and laying-type chickens. A large amount of ATP is required during skeletal muscle synthesis, in which mitochondrial energy production capacities play a significant role. Additionally, mitochondria may participate in muscle protein degradation via reactive oxygen species generation. To investigate the differences in mitochondrial energetic characteristics between chickens exhibiting different growth rates, this study evaluated respiratory capacities in response to different types of respiratory substrate, protein abundances, assembly of individual respiratory complexes (I–V) and supercomplexes, and reactive oxygen species generation rates. These characteristics were compared between mitochondria from the breast muscle (M. pectoralis superficialis) of seven-week-old meat- and laying-type male chickens. Blue native polyacrylamide gel electrophoresis analysis revealed that meat-type chickens exhibited a significantly lower protein abundance of complex III (cytochrome bc1 complex), complex V (F0F1 ATP synthase), and total amount of supercomplexes than did laying-type chickens. There were no differences between chicken types in the respiration rate of mitochondria incubated with either pyruvate/malate or succinate, each of which drives complex I- and complex II-linked respiration. Carnitine palmitoyltransferase-1-dependent and -independent respiration during ATP synthesis and carnitine palmitoyltransferase-2 enzymatic activity were significantly lower in meat-type chickens than in layingtype chickens. For mitochondria receiving pyruvate/malate plus succinate, the reactive oxygen species generation rate and its ratio to the oxygen consumed (the percentage of free radical leak) were also significantly lower in meat-type chickens than in laying-type chickens. These results suggested that the mitochondrial energetic capacities of the breast muscle of meat-type chickens could be lower than those of laying-type chickens at seven weeks of age. Furthermore, the lower reactive oxygen species generation rate in meat-type chickens might have implications for rapid muscle development, which is possibly related to their lower muscle protein degradation rates

Lipid peroxidation (A) and protein carbonyl (B) in the <i>pectoralis superficialis</i> muscle.

<p>Lipid peroxidation was colorimetrically determined using a conventional TBARS assay. To determine protein carbonyl content by derivatization with DNPH, an additional experiment was similarly conducted. All measurements were carried out as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064412#s2" target="_blank">Materials and Methods</a>. Values are means ± SE of data from eight individual tissue samples. *<i>P</i><0.05 compared to control group.</p

Effect of arachidonic acid and GDP on proton leak kinetics of skeletal muscle mitochondria isolated from control (open symbols) and heat-stressed (filled symbols) birds.

<p>Basal (circles) and arachidonic acid-induced (36 μM, diamonds) proton leak kinetics in both groups (A). Inhibitory effect of GDP (500 μM, squares) on the arachidonic acid-induced proton leak in control (B) and heat-stressed (C) groups. Mitochondria (0.35 mg protein/ml) were energized by 4 mM succinate in assay medium B containing 0.1 μM nigericin and 1 μg/ml oligomycin, and titrated with sequential additions of malonate (up to 3.2 mM). Value are means ± S.E. of four individual measurements in each group.</p