Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency

Energy production via the mitochondrial electron transport chain (ETC) and mitophagy are two important processes affected in Parkinson’s disease (PD). Interestingly, PINK1, mutations of which cause early-onset PD, plays a key role in both processes, suggesting that these two mechanisms are connected. However, the converging link of both pathways currently remains enigmatic. Recent findings demonstrated that lipid aggregation, along with defective mitochondria, is present in postmortem brains of PD patients. In addition, an increasing body of evidence shows that sphingolipids, including ceramide, are altered in PD, supporting the importance of lipids in the pathophysiology of PD. Here, we identified ceramide to play a crucial role in PINK1-related PD that was previously linked almost exclusively to mitochondrial dysfunction. We found ceramide to accumulate in mitochondria and to negatively affect mitochondrial function, most notably the ETC. Lowering ceramide levels improved mitochondrial phenotypes in pink1-mutant flies and PINK1-deficient patient-derived fibroblasts, showing that the effects of ceramide are evolutionarily conserved. In addition, ceramide accumulation provoked ceramide-induced mitophagy upon PINK1 deficiency. As a result of the ceramide accumulation, β-oxidation in PINK1 mutants was decreased, which was rescued by lowering ceramide levels. Furthermore, stimulation of β-oxidation was sufficient to rescue PINK1-deficient phenotypes. In conclusion, we discovered a cellular mechanism resulting from PD-causing loss of PINK1 and found a protective role of β-oxidation in ETC dysfunction, thus linking lipids and mitochondria in the pathophysiology of PINK1-related PD. Furthermore, our data nominate β-oxidation and ceramide as therapeutic targets for PD.

Loss of PINK1 function causes autosomal recessive early-onset Parkinson’s disease (PD). Most patients present with bradykinesia, rigidity, resting tremor, and dyskinesia and are responsive to dopamine replacement therapy (1). On the cellular level, PINK1 disease mutations result in impaired energy metabolism and a variety of mitochondrial defects that can partially be alleviated by stimulation of energy metabolism (2–4). Intriguingly, abnormal mitochondrial morphology, along with lipid aggregates, was recently discovered to be present in Lewy bodies of postmortem PD patients’ brains (5), challenging the previously held notion of alpha-synuclein being the almost exclusive neuropathological correlate. This finding confirms the involvement of mitochondrial dysfunction in PD and additionally suggests a critical role of lipids in the pathogenesis of PD.PINK1 is important for the phosphorylation of the Complex I subunit NdufA10 resulting in efficient Complex I and electron transport chain (ETC) activity (6, 7). This function is evolutionarily conserved between Drosophila and humans. Hence, in both flies and humans, loss of PINK1 results in an impaired ETC, reduced ATP levels, and defective mitochondrial morphology (6, 8, 9), all of which are ubiquitously observed in the fly already at the early larval stage. Furthermore, alongside Parkin, PINK1 plays a crucial role in mitophagy to remove defective mitochondria that appears to be defective in an age-dependent fashion (10–13). Pink1-mutant Drosophila melanogaster additionally show thorax muscle degeneration and defective flying ability (8, 9). These latter defects, together with impaired mitochondrial morphology, can be rescued by expressing the fission-promoting protein Drp1 (14). However, increased fission does not improve ETC-related defects (15). Furthermore, stimulation or facilitation of the ETC rescues ETC-related phenotypes in pink1-mutant Drosophila, including ATP levels and mitochondrial morphology (3, 4, 7, 15, 16). These data collectively suggest two parallel mechanisms that converge on a shared common pathway leading to the development of PD. However, the link between these two pathways has yet to be resolved.Recently, disrupted lipid homeostasis has garnered increasing attention in PD (16–18). Furthermore, ceramide, the basic sphingolipid, is altered in several PD models and has been implicated in PD-related alpha-synuclein toxicity (17–20). Interestingly, ceramide induces mitophagy that is facilitated by Drp1 (21). Furthermore, pathogenic variants in Glucocerebrosidase (GCase), an enzyme involved in ceramide synthesis, are known to be the most common risk factor for PD (22, 23). However, the exact mechanism remains enigmatic. We found increased ceramide levels in isolated mitochondria of Pink1^−/− knockout (KO) mouse embryonic fibroblasts (MEFs) (16) and Pink1-deficient flies. Increased ceramide levels are detrimental for proper ETC function (24). Hence, we hypothesize that ceramide accumulation in PINK1 deficiency affects ETC function and mitophagy and constitutes the missing link between these two important processes affected in PD.     

Complete genome sequence analysis of temperate Erwinia bacteriophages 49 and 59

To date, a small number of temperate phages are known to infect members of the genus Erwinia. In this study, the genomes of temperate phages vB_EhrS_49 and vB_EhrS_59 infecting Erwinia horticola, the causative agent of beech black bacteriosis in Ukraine, were sequenced and annotated. Their genomes reveal no significant similarity to that of any previously reported viruses of Enterobacteriaceae. At the same time, phages 49 and 59 share extensive nucleotide sequence identity across the regions encoding head assembly, DNA packaging, and lysis. Despite significant homology between structural modules, the organization of distal tail morphogenesis genes is different. Furthermore, a number of putative morons and DNA methylases have been found in both phage genomes. Due to the revealed synteny as well as the structure of lysogeny module, phages 49 and 59 are suggested to be novel members of the lambdoid phage group. Conservative structural genes together with varying homology across the nonstructural region of the genomes make phages 49 and 59 highly promising objects for studying the genetic recombination and evolution of microbial viruses. The obtained data may as well be helpful for better understanding of relationships among Erwinia species.     

The Characterization of Ukrainian Volcanic Tuffs from the Khmelnytsky Region with the Theoretical Analysis of Their Application in Construction and Environmental Technologies

(1) The mineral deposits are the base resources of materials used in building and environmental engineering applications, especially available locally. Two wells of volcanic tuff deposits in the Khmelnytsky region of Ukraine were investigated in this regard. (2) Physical-mechanical, chemical, and mineralogical analyses of the core samples were carried out. (3) The tuff samples were characterized by visible colour, low compressive strength (4.34–11.13 MPa), and high water absorption (30%). The dominant minerals of the upper horizon were chlorite, pyroxene, kaolinite, quartz, hematite, and calcite, while those of the lower horizon included analcime, quartz, hematite, and calcite. (4) The studied volcanic tuffs seem to be only partly useful for construction applications, and considering their visible colour, the exterior decoration of engineering objects could be possible. The peculiarity of the minerals of the upper horizon is that their crystals consist of Fe²⁺. An analysis of existing scientific data made it possible to say that these minerals can be considered as an alternative to expensive metallic iron in reducing the toxicity of chromium, uranium, and halogenated organic compounds. The significant presence of hematite allows the application of tuffs to technologies of water purification from As⁵⁺, As³⁺, Cr⁶⁺, Cr³⁺, U⁶⁺, Sb⁵⁺, and Se⁴⁺ oxyanions.     

Links between unit costs for HIV services,perceived service quality and client satisfaction in Ukraine

Journal of Public Health - Ukraine’s HIV prevention and management efforts focus on continuous and sustained scale-up of services. To reach UNAIDS 90–90-90 targets by 2020, Ukraine...     

Highbush Blueberry (Vaccinium corymbosum L.) Leaves Extract and Its Modified Arginine Preparation for the Management of Metabolic Syndrome—Chemical Analysis and Bioactivity in Rat Model

Growing blueberry (Vaccinium corymbosum L., Highbush blueberry) as a berry crop is developing dynamically, especially in warm temperate, subtropical, and tropical regions of the world. When blueberry is cultivated on plantations, the bushes are pruned annually, and tons of leaves become waste. Thus, the aim of the present study was to create a preparation from blueberry leaves, study their chemical composition and determine their potential as a dietary supplement for the prophylactic and correction of the metabolic syndrome. Several schemes for obtaining extracts from blueberry leaves have been developed, including one with addition of arginine. A total of 18 phenolic substances were identified and quantified in the extracts by TLC and HPLC methods. Chlorogenic acid, hyperoside, and rutin were shown to be dominating constituents. Quantitative determination of hydroxycinnamic acid derivatives, flavonoids and other phenolics in the extracts was performed by spectrophotometric method. The extracts administration led to a significant decrease in the level of glucose, insulin and triacylglycerols in blood serum of adult mature inbred rats with insulin resistance induced by the fructose-enriched diet. The most promising one was the extract modified with arginine. The determined hypoglycemic and hypolipidemic activity of chemically standardized extracts from highbush blueberry leaves indicate the potential of this crop residue in utilization as a dietary supplement recommended in prevention of ailments associated with metabolic syndrome.     

Structural and Tribological Assessment of Biomedical 316 Stainless Steel Subjected to Pulsed-Plasma Surface Modification: Comparison of LPBF 3D Printing and Conventional Fabrication

The structural features and nanoindentation/tribological properties of 316 stainless steel fabricated by conventional rolling and laser-based powder bed fusion (LPBF) were comparatively investigated regarding the effect of surface-pulsed plasma treatment (PPT). PPT was performed using an electrothermal axial plasma accelerator under a discharge voltage of 4.5 kV and a pulse duration of 1 ms. Optical microscopy, scanning electron microscopy, X-ray diffraction, nanoindentation measurements and tribological tests were applied to characterize the alloys. The LPBF steel presented almost the same modulus of elasticity and double the hardness of rolled steel. However, the LPBF steel manifested lower dry-sliding wear resistance compared with its wrought counterpart due to its porous structure and non-metallic inclusions. Conversely, LPBF steel showed three times higher wear resistance under sliding in simulated body fluid (SBF), as compared with wrought steel. PPT led to steel modification through surface melting to a depth of 22–26 μm, which resulted in a fine cellular structure. PPT moderately improved the dry-sliding wear resistance of LPBF steel by fusion of pores on its surface. On the other hand, PPT had almost no effect on the SBF-sliding wear response of the steel. The modification features were analyzed using a computer simulation of plasma-induced heating.     

Correction to: The child and adolescent psychiatry: study of training in Europe (CAP‑STATE)

The original article has been corrected.     

The child and adolescent psychiatry: study of training in Europe (CAP-STATE)

European Child & Adolescent Psychiatry - There is great cultural diversity across Europe. This is reflected in the organisation of child and adolescent mental health (CAMH) services and the...