Neurodegeneration as a consequence of failed mitochondrial maintenance

Maintaining the functional integrity of mitochondria is pivotal for cellular survival. It appears that neuronal homeostasis depends on high-fidelity mitochondria, in particular. Consequently, mitochondrial dysfunction is a fundamental problem associated with a significant number of neurological diseases, including Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and various peripheral neuropathies, as well as the normal aging process. To ensure optimal mitochondrial function, diverse, evolutionarily conserved mitochondrial quality control mechanisms are in place, including the scavenging of toxic reactive oxygen species (ROS) and degradation of damaged mitochondrial proteins, but also turnover of whole organelles. In this review we will discuss various mitochondria-associated conditions, focusing on the role of protein turnover in mitochondrial maintenance with special emphasis on neurodegenerative disorder

The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division

We identify a mitochondrial E3 ubiquitin ligase, MARCH5, as a critical regulator of mitochondrial fission. MARCH5 RING mutants and MARCH5 RNA interference induce an abnormal elongation and interconnection of mitochondria indicative of an inhibition of mitochondrial division. The aberrant mitochondrial phenotypes in MARCH5 RING mutant–expressing cells are reversed by ectopic expression of Drp1, but not another mitochondrial fission protein Fis1. Moreover, as indicated by abnormal clustering and mitochondrial accumulation of Drp1, as well as decreased cellular mobility of YFP-Drp1 in cells expressing MARCH5 RING mutants, MARCH5 activity regulates the subcellular trafficking of Drp1, likely by impacting the correct assembly at scission sites or the disassembly step of fission complexes. Loss of this activity may account for the observed mitochondrial division defects. Finally, MARCH5 RING mutants and endogenous Drp1, but not wild-type MARCH5 or Fis1, co-assemble into abnormally enlarged clusters in a Drp1 GTPase-dependent manner, suggesting molecular interactions among these proteins. Collectively, our data suggest a model in which mitochondrial division is regulated by a MARCH5 ubiquitin-dependent switch

Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis

A dynamic balance of organelle fusion and fission regulates mitochondrial morphology. During apoptosis this balance is altered, leading to an extensive fragmentation of the mitochondria. Here, we describe a novel assay of mitochondrial dynamics based on confocal imaging of cells expressing a mitochondrial matrix–targeted photoactivable green fluorescent protein that enables detection and quantification of organelle fusion in living cells. Using this assay, we visualize and quantitate mitochondrial fusion rates in healthy and apoptotic cells. During apoptosis, mitochondrial fusion is blocked independently of caspase activation. The block in mitochondrial fusion occurs within the same time range as Bax coalescence on the mitochondria and outer mitochondrial membrane permeabilization, and it may be a consequence of Bax/Bak activation during apoptosis

Endophilin B1 is required for the maintenance of mitochondrial morphology

We report that a fatty acyl transferase, endophilin B1, is required for maintenance of mitochondrial morphology. Down-regulation of this protein or overexpression of endophilin B1 lacking the NH2-terminal lipid-modifying domain causes striking alterations of the mitochondrial distribution and morphology. Dissociation of the outer mitochondrial membrane compartment from that of the matrix, and formation of vesicles and tubules of outer mitochondrial membrane, was also observed in both endophilin B1 knockdown cells and after overexpression of the truncated protein, indicating that endophilin B1 is required for the regulation of the outer mitochondrial membrane dynamics. We also show that endophilin B1 translocates to the mitochondria during the synchronous remodeling of the mitochondrial network that has been described to occur during apoptosis. Double knockdown of endophilin B1 and Drp1 leads to a mitochondrial phenotype identical to that of the Drp1 single knockdown, a result consistent with Drp1 acting upstream of endophilin B1 in the maintenance of morphological dynamics of mitochondria

Co-existence of apoptotic and necrotic features within one single cell as a result of menadione treatment

In the present study we examined the effects of menadione, a redox cycling agent, on structural changes of human osteosarcoma line 143B cells. It has been previously reported that menadione can cause necrotic or apoptotic cell death in a concentration- depending manner. In our experimental model, cells were treated with 100 μM menadione for 24 hours. Using electron microscopy technique cells carrying three kinds of morphological changes were detected: necrotic cells, apoptotic cells and those demonstrating a co-existence of apoptotic and necrotic features in one single cell

Wyłaniające się odmiany kapitalizmu w Europie Środkowo-Wschodniej: przegląd badań

The article contains a review of the most representative theoretical and empirical studies on the emerging varieties/models of capitalism in Central Eastern Europe (CEE). A critical appraisal was made of standard and non-standard approaches found in the subject literature. Specific features of the institutional structure existing in the CEE countries have been indicated which make it difficult to apply the theoretical framework used in the developed capitalist countries. Possible directions of further research on the models of capitalism emerging in CEE have also been delineated together with some proposals of modification and extension of the theoretical and methodological framework of this research

Wyłaniające się odmiany kapitalizmu w Europie Środkowo-Wschodniej: przegląd badań

The article contains a review of the most representative theoretical and empirical studies on the emerging varieties/models of capitalism in Central Eastern Europe (CEE). A critical appraisal was made of standard and non-standard approaches found in the subject literature. Specific features of the institutional structure existing in the CEE countries have been indicated which make it difficult to apply the theoretical framework used in the developed capitalist countries. Possible directions of further research on the models of capitalism emerging in CEE have also been delineated together with some proposals of modification and extension of the theoretical and methodological framework of this research

Wyłaniające się modele kapitalizmu w Polsce i krajach Europy Środkowo-Wschodniej na tle Europy Zachodniej

This article presents the results of the study which aims to enrich the empirical picture and to better understand the nature of capitalism emerging in Poland and other new EU member states from Central and Eastern Europe (CEE11). Our main research goal is to assess the degree of similarity of Poland and other CEE11 countries toward each of the four models of capitalism in Western Europe distinguished by Bruno Amable. Each of these models is represented by an “ideal-typical” western European country. At the average level for the whole analyzed group, the CEE11 countries show the greatest similarity to the Mediterranean model of capitalism, represented by Spain/Italy. At the same time, these countries also exhibit quite high institutional proximity to the continental model of capitalism, represented by Germany