Dopamine and Methamphetamine Differentially Affect Electron Transport Chain Complexes and Parkin in Rat Striatum: New Insight into Methamphetamine Neurotoxicity

Methamphetamine (METH) is a highly abused psychostimulant that is neurotoxic to dopaminergic (DAergic) nerve terminals in the striatum and increases the risk of developing Parkinson’s disease (PD). In vivo, METH-mediated DA release, followed by DA-mediated oxidative stress and mitochondrial dysfunction in pre- and postsynaptic neurons, mediates METH neurotoxicity. METH-triggered oxidative stress damages parkin, a neuroprotective protein involved in PD etiology via its involvement in the maintenance of mitochondria. It is not known whether METH itself contributes to mitochondrial dysfunction and whether parkin regulates complex I, an enzymatic complex downregulated in PD. To determine this, we separately assessed the effects of METH or DA alone on electron transport chain (ETC) complexes and the protein parkin in isolated striatal mitochondria. We show that METH decreases the levels of selected complex I, II, and III subunits (NDUFS3, SDHA, and UQCRC2, respectively), whereas DA decreases the levels only of the NDUFS3 subunit in our preparations. We also show that the selected subunits are not decreased in synaptosomal mitochondria under similar experimental conditions. Finally, we found that parkin overexpression does not influence the levels of the NDUFS3 subunit in rat striatum. The presented results indicate that METH itself is a factor promoting dysfunction of striatal mitochondria; therefore, it is a potential drug target against METH neurotoxicity. The observed decreases in ETC complex subunits suggest that DA and METH decrease activities of the ETC complexes via oxidative damage to their subunits and that synaptosomal mitochondria may be somewhat “resistant” to DA- and METH-induced disruption in mitochondrial ETC complexes than perikaryal mitochondria. The results also suggest that parkin does not regulate NDUFS3 turnover in rat striatum.

Cut cotorsion pairs

We present the concept of cotorsion pairs cut along subcategories of an abelian category. This provides a generalization of complete cotorsion pairs, and represents a general framework to find approximations restricted to certain subcategories. We also exhibit some connections between cut cotorsion pairs and Auslander–Buchweitz approximation theory, by considering relative analogs for Frobenius pairs and Auslander–Buchweitz contexts. Several applications are given in the settings of relative Gorenstein homological algebra, chain complexes, and quasi-coherent sheaves, as well as to characterize some important results on the Finitistic Dimension Conjecture, the existence of right adjoints of quotient functors by Serre subcategories, and the description of cotorsion pairs in triangulated categories as co-t-structures.

The Assembly of Super-Complexes in the Plant Chloroplast

Increasing evidence has revealed that the enzymes of several biological pathways assemble into larger supramolecular structures called super-complexes. Indeed, those such as association of the mitochondrial respiratory chain complexes play an essential role in respiratory activity and promote metabolic fitness. Dynamically assembled super-complexes are able to alternate between participating in large complexes and existing in a free state. However, the functional significance of the super-complexes is not entirely clear. It has been proposed that the organization of respiratory enzymes into super-complexes could reduce oxidative damage and increase metabolism efficiency. There are several protein complexes that have been revealed in the plant chloroplast, yet little research has been focused on the formation of super-complexes in this organelle. The photosystem I and light-harvesting complex I super-complex’s structure suggests that energy absorbed by light-harvesting complex I could be efficiently transferred to the PSI core by avoiding concentration quenching. Here, we will discuss in detail core complexes of photosystem I and II, the chloroplast ATPase the chloroplast electron transport chain, the Calvin–Benson cycle and a plastid localized purinosome. In addition, we will also describe the methods to identify these complexes.

Bacterial respiration keeps amazing us in the 21st century

The last two decades have seen some remarkable discoveries in bacterial bioenergetics. In this article, we highlight how important societal issues such as antimicrobial resistance and sustainable fuel production have led to a renewed focus on the bioenergetics of bacteria, which is only beginning to show us how much we have left to learn. Advances in technology, particularly through biophysics, have further contributed to a rapid progress in our understanding of the respiratory chain complexes in bacteria. Blue-sky research has seamlessly merged with solutions to societal problems and we stand on the precipice of a number of exciting discoveries in this field.

The FASTK family proteins fine-tune mitochondrial RNA processing

Transcription of the human mitochondrial genome and correct processing of the two long polycistronic transcripts are crucial for oxidative phosphorylation. According to the tRNA punctuation model, nucleolytic processing of these large precursor transcripts occurs mainly through the excision of the tRNAs that flank most rRNAs and mRNAs. However, some mRNAs are not punctuated by tRNAs, and it remains largely unknown how these non-canonical junctions are resolved. The FASTK family proteins are emerging as key players in non-canonical RNA processing. Here, we have generated human cell lines carrying single or combined knockouts of several FASTK family members to investigate their roles in non-canonical RNA processing. The most striking phenotypes were obtained with loss of FASTKD4 and FASTKD5 and with their combined double knockout. Comprehensive mitochondrial transcriptome analyses of these cell lines revealed a defect in processing at several canonical and non-canonical RNA junctions, accompanied by an increase in specific antisense transcripts. Loss of FASTKD5 led to the most severe phenotype with marked defects in mitochondrial translation of key components of the electron transport chain complexes and in oxidative phosphorylation. We reveal that the FASTK protein family members are crucial regulators of non-canonical junction and non-coding mitochondrial RNA processing.

Mycolactone enhances the Ca2+ leakage from endoplasmic reticulum by trapping Sec61 translocons in a Ca2+ permeable state

The Mycobacterium ulcerans exotoxin, mycolactone, is an inhibitor of co-translational translocation via the Sec61 complex. Mycolactone has previously been shown to bind to, and alter the structure of, the major translocon subunit Sec61α, and change its interaction with ribosome nascent chain complexes. In addition to its function in protein translocation into the ER, Sec61 also plays a key role in cellular Ca2+ homeostasis, acting as a leak channel between the endoplasmic reticulum (ER) and cytosol. Here, we have analysed the effect of mycolactone on cytosolic and ER Ca2+ levels using compartment-specific sensors. We also used molecular docking analysis to explore potential interaction sites for mycolactone on translocons in various states. These results show that mycolactone enhances the leak of Ca2+ ions via the Sec61 translocon, resulting in a slow but substantial depletion of ER Ca2+. This leak was dependent on mycolactone binding to Sec61α because resistance mutations in this protein completely ablated the increase. Molecular docking supports the existence of a mycolactone-binding transient inhibited state preceding translocation and suggests mycolactone may also bind Sec61α in its idle state. We propose that delayed ribosomal release after translation termination and/or translocon “breathing” during rapid transitions between the idle and intermediate-inhibited states allow for transient Ca2+ leak, and mycolactone’s stabilisation of the latter underpins the phenotype observed.

New model structures and projective (injective) cotorsion pairs

Let [Formula: see text] be either the category of [Formula: see text]-modules or the category of chain complexes of [Formula: see text]-modules and [Formula: see text] a cofibrantly generated hereditary abelian model structure on [Formula: see text]. First, we get a new cofibrantly generated model structure on [Formula: see text] related to [Formula: see text] for any positive integer [Formula: see text], and hence, one can get new algebraic triangulated categories. Second, it is shown that any [Formula: see text]-strongly Gorenstein projective module gives rise to a projective cotorsion pair cogenerated by a set. Finally, let [Formula: see text] be an [Formula: see text]-module with finite flat dimension and [Formula: see text] a positive integer, if [Formula: see text] is an exact sequence of [Formula: see text]-modules with every [Formula: see text] Gorenstein injective, then [Formula: see text] is injective.

RNA Granules in the Mitochondria and Their Organization under Mitochondrial Stresses

The human mitochondrial genome (mtDNA) regulates its transcription products in specialised and distinct ways as compared to nuclear transcription. Thanks to its mtDNA mitochondria possess their own set of tRNAs, rRNAs and mRNAs that encode a subset of the protein subunits of the electron transport chain complexes. The RNA regulation within mitochondria is organised within specialised, membraneless, compartments of RNA-protein complexes, called the Mitochondrial RNA Granules (MRGs). MRGs were first identified to contain nascent mRNA, complexed with many proteins involved in RNA processing and maturation and ribosome assembly. Most recently, double-stranded RNA (dsRNA) species, a hybrid of the two complementary mRNA strands, were found to form granules in the matrix of mitochondria. These RNA granules are therefore components of the mitochondrial post-transcriptional pathway and as such play an essential role in mitochondrial gene expression. Mitochondrial dysfunctions in the form of, for example, RNA processing or RNA quality control defects, or inhibition of mitochondrial fission, can cause the loss or the aberrant accumulation of these RNA granules. These findings underline the important link between mitochondrial maintenance and the efficient expression of its genome.