Mitochondrial function and autophagy: integrating proteotoxic,redox, and metabolic stress in Parkinson's disease

Parkinson's disease (PD) is a movement disorder with widespread neurodegeneration in the brain. Significant oxidative, reductive, metabolic, and proteotoxic alterations have been observed in PD postmortem brains. The alterations of mitochondrial function resulting in decreased bioenergetic health is important and needs to be further examined to help develop biomarkers for PD severity and prognosis. It is now becoming clear that multiple hits on metabolic and signaling pathways are likely to exacerbate PD pathogenesis. Indeed, data obtained from genetic and genome association studies have implicated interactive contributions of genes controlling protein quality control and metabolism. For example, loss of key proteins that are responsible for clearance of dysfunctional mitochondria through a process called mitophagy has been found to cause PD, and a significant proportion of genes associated with PD encode proteins involved in the autophagy‐lysosomal pathway. In this review, we highlight the evidence for the targeting of mitochondria by proteotoxic, redox and metabolic stress, and the role autophagic surveillance in maintenance of mitochondrial quality. Furthermore, we summarize the role of α‐synuclein, leucine‐rich repeat kinase 2, and tau in modulating mitochondrial function and autophagy. Among the stressors that can overwhelm the mitochondrial quality control mechanisms, we will discuss 4‐hydroxynonenal and nitric oxide. The impact of autophagy is context depend and as such can have both beneficial and detrimental effects. Furthermore, we highlight the potential of targeting mitochondria and autophagic function as an integrated therapeutic strategy and the emerging contribution of the microbiome to PD susceptibility.

     

The ecological integrity of the lower Olifants River,Limpopo province,South Africa: 2009–2015 – Part B: Tributaries of the Olifants River

Monitoring on the Lowveld reaches of the Olifants River, Limpopo River System, and its Steelpoort, Blyde, Klaserie and Selati tributaries was initiated in 2009. Analysis of the 2009–2015 data from four Olifants River sites showed deterioration in the river’s ecological condition between where it enters the Lowveld and where it enters the Kruger National Park, with a slight recovery within the Kruger National Park. Physico-chemical, aquatic macroinvertebrate and fish data collected in 2009–2015 at six sites on the Steelpoort, Blyde, Klaserie and Selati tributaries of the Olifants River corroborated the ecological condition of these tributaries. The Selati was the most polluted and was in a critically modified condition, whereas the Klaserie and Steelpoort were in fair condition and the Blyde was in good condition. The Selati appeared to have a significant negative impact on the water quality, macroinvertebrates and fish of the Olifants River within the Kruger National Park.     

Dietary Patterns and the Metabolic Syndrome in Obese and Non‐obese Framingham Women**

Objectives: To examine the relationship between habitual dietary patterns and the metabolic syndrome (MetS) in women and to identify foci for preventive nutrition interventions. Research Methods and Procedures: Dietary patterns, nutrient intake, cardiovascular disease (CVD), and MetS risk factors were characterized in 1615 Framingham Offspring‐Spouse Study (FOS) women. Dietary pattern subgroups were compared for MetS prevalence and CVD risk factor status using logistic regression and analysis of covariance. Analyses were performed overall in women and stratified on obesity status; multivariate models controlled for age, apolipoprotein E (APOE) genotypes, and CVD risk factors. Results: Food and nutrient profiles and overall nutritional risk of five non‐overlapping habitual dietary patterns of women were identified including Heart Healthier, Lighter Eating, Wine and Moderate Eating, Higher Fat, and Empty Calories. Rates of hypertension and low high‐density lipoprotein levels were high in non‐obese women, but individual MetS risk factor levels were substantially increased in obese women. Overall MetS risk varied by dietary pattern and obesity status, independently of APOE and CVD risk factors. Compared with obese or non‐obese women and women overall with other dietary patterns, MetS was highest in those with the Empty Calorie pattern (contrast p value: p < 0.05). Discussion: This research shows the independent relationship between habitual dietary patterns and MetS risk in FOS women and the influence of obesity status. High overall MetS risk and the varying prevalence of individual MetS risk factors in female subgroups emphasize the importance of preventive nutrition interventions and suggest potential benefits of targeted behavior change in both obese and non‐obese women by dietary pattern.     

A novel chromatography system to isolate active ribosomes from pathogenic bacteria

We have developed a novel chromatography for the rapid isolation of active ribosomes from bacteria without the use of harsh conditions or lengthy procedures that damage ribosomes. Ribosomes interact with an alkyl linker attached to the resin, apparently through their RNA component. Examples are given with ribosomes from Escherichia coli, Deinococcus radiodurans, and with clinical isolates of Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). The ribosomes obtained by this method are unusually intact, so that highly active ribosomes can now be isolated from the clinical isolates, enabling significantly improved in vitro functional assays that will greatly assist the discovery and development of new ribosomally targeted antibiotics.     

gamma-Tocopherol nebulization by a lipid aerosolization device improves pulmonary function in sheep with burn and smoke inhalation injury

Fire accident victims who sustain both thermal injury to skin and smoke inhalation have gross evidence of systemic and pulmonary oxidant damage and acute lung injury. We hypothesized that gamma-tocopherol (gT), a reactive O(2) and N(2) scavenger, when delivered into the airway, would attenuate lung injury induced by burn and smoke inhalation. Acute lung injury was induced in chronically prepared, anesthetized sheep by 40% total burn surface area, third-degree skin burn and smoke insufflation (48 breaths of cotton smoke, <40 degrees C). The study groups were: (1) Sham (not injured, flaxseed oil (FO)-nebulized, n=6); (2) SA-neb (injured, saline-nebulized, n=6); (3) FO-neb (injured, FO-nebulized, n=6); and (4) gT+FO-neb (injured, gT and FO-nebulized, n=6). Nebulization was started 1 h postinjury, and 24 ml of FO with or without gT (51 mg/ml) was delivered into airways over 47 h using our newly developed lipid aerosolization device (droplet size: 2.5-5 microm). The burn- and smoke inhalation-induced pathological changes seen in the saline group were attenuated by FO nebulization; gT addition further improved pulmonary function. Pulmonary gT delivery along with a FO source may be a novel effective treatment strategy in management of patients with acute lung injury.     

Expression of the <Emphasis Type="Italic">yggE</Emphasis> gene protects <Emphasis Type="Italic">Escherichia coli</Emphasis> from potassium tellurite-generated oxidative stress

Potassium tellurite is highly toxic to most forms of life and specific bacterial tellurite defense mechanisms are not fully understood to date. Recent evidence suggests that tellurite would exert its toxic effects, at least in part, through the generation of superoxide anion that occurs concomitantly with intracellular tellurite (Te⁴⁺) reduction to elemental tellurium (Te^o). In this work the putative antioxidant role of YggE from Escherichia coli, a highly conserved protein in several bacterial species and whose function is still a matter of speculation, was studied. When exposed to tellurite, E. coli lacking yggE exhibited increased activity of superoxide dismutase and fumarase C, augmented levels of reactive oxygen species and high concentration of carbonyl groups in proteins. Upon genetic complementation with the homologous yggE gene these values were restored to those observed in the parental, isogenic, wild type strain, suggesting a direct participation of YggE in E. coli tolerance to tellurite.     

Dynamic evolution of the human immunodeficiency virus type 1 pathogenic factor, Nef

The human immunodeficiency virus type 1 (HIV-1) early gene product Nef is a multifunctional protein that alters numerous pathways of T-cell function, including endocytosis, signal transduction, vesicular trafficking, and immune modulation, and is a major determinant of pathogenesis. Individual Nef functions include PAK-2 activation, CD4 downregulation, major histocompatibility complex (MHC) class I downregulation, and enhancement of viral particle infectivity. How Nef accomplishes its multiple tasks presents a difficult problem of mechanistic analysis because of the complications associated with multiple, overlapping functional domains in the context of significant sequence variability. To address these issues we determined the conservation of each Nef residue based on 1,643 subtype B Nef sequences. Mutational analysis based on conservative substitutions and Nef sequence data allowed us to search for amino acids on the surface of Nef that are specifically required for PAK-2 activation. We found residues 85, 89, and 191 to be highly significant determinants for Nef's PAK-2 activation function but functionally unlinked to CD4 and MHC class I downregulation or enhancement of infectivity. These residues are not conserved across HIV-1 subtypes but are confined to separate sets of surface elements within a subtype. Thus, L85/H89/F191 and F85/F89/R191 are dominant in subtype B and subtype E or C, respectively. Our results provide support for developing subtype-specific interventions in HIV-1 disease.     

Parasite-mediated enemy release and low biotic resistance may facilitate invasion of Atlantic coral reefs by Pacific red lionfish (<Emphasis Type="Italic">Pterois volitans</Emphasis>)

Successful invasions are largely explained by some combination of enemy release, where the invader escapes its natural enemies from its native range, and low biotic resistance, where native species in the introduced range fail to control the invader. We examined the extent to which parasites may mediate both release and resistance in the introduction of Pacific red lionfish (Pterois volitans) to Atlantic coral reefs. We found that fewer lionfish were parasitized at two regions in their introduced Atlantic range (The Bahamas and the Cayman Islands) than at two regions in their native Pacific range (the Northern Marianas Islands and the Philippines). This pattern was largely driven by relatively high infection rates of lionfish by didymozoan fluke worms and parasitic copepods (which may be host-specific to Pterois lionfishes) in the Marianas and the Philippines, respectively. When compared with sympatric, native fishes in the Atlantic, invasive lionfish were at least 18 times less likely to host a parasite in The Bahamas and at least 40 times less likely to host a parasite in the Cayman Islands. We found no indication that lionfish introduced Pacific parasites into the Atlantic. In conjunction with demographic signs of enemy release such as increased density, fish size, and growth of invasive lionfish, it is possible that escape from parasites may have contributed to the success of lionfish. This is especially true if future studies reveal that such a loss of parasites has led to more energy available for lionfish growth, reproduction, and/or immunity.     

Isolation and genetic characterization of a relapsing fever spirochete isolated from Ornithodoros puertoricensis collected in central Panama

Tick-borne relapsing fever (TBRF) spirochetes are likely an overlooked cause of disease in Latin America. In Panama, the pathogens were first reported to cause human disease in the early 1900s. Recent collections of Ornithodoros puertoricensis from human dwellings in Panama prompted our interest to determine whether spirochetes still circulate in the country. Ornithodoros puertoricensis ticks were collected at field sites around the City of Panama. In the laboratory, the ticks were determined to be infected with TBRF spirochetes by transmission to mice, and we report the laboratory isolation and genetic characterization of a species of TBRF spirochete from Panama. Since this was the first isolation of a species of TBRF spirochete from Central America, we propose to designate the bacteria as Borrelia puertoricensis sp. nov. This is consistent with TBRF spirochete species nomenclature from North America that are designated after their tick vector. These findings warrant further investigations to assess the threat B. puertoricensis sp. nov. may impose on human health.