Adaptive antioxidant methionine accumulation in respiratory chain complexes explains the use of a deviant genetic code in mitochondria

Humans and most other animals use 2 different genetic codes to translate their hereditary information: the standard code for nuclear-encoded proteins and a modern variant of this code in mitochondria. Despite the pivotal role of the genetic code for cell biology, the functional significance of the deviant mitochondrial code has remained enigmatic since its first description in 1979. Here, we show that profound and functionally beneficial alterations on the encoded protein level were causative for the AUA codon reassignment from isoleucine to methionine observed in most mitochondrial lineages. We demonstrate that this codon reassignment leads to a massive accumulation of the easily oxidized amino acid methionine in the highly oxidative inner mitochondrial membrane. This apparently paradoxical outcome can yet be smoothly settled if the antioxidant surface chemistry of methionine is taken into account, and we present direct experimental evidence that intramembrane accumulation of methionine exhibits antioxidant and cytoprotective properties in living cells. Our results unveil that methionine is an evolutionarily selected antioxidant building block of respiratory chain complexes. Collective protein alterations can thus constitute the selective advantage behind codon reassignments, which authenticates the “ambiguous decoding” hypothesis of genetic code evolution. Oxidative stress has shaped the mitochondrial genetic code

Molekulare Grundlagen Tau-Protein-vermittelter Toxizität : neue experimentelle Therapiestrategien zur Behandlung der Alzheimer-Erkrankung

Neurofibrillen sind neben den amyloiden Plaques die histopathologischen Kennzeichen der Alzheimer-Erkrankung. Sie bestehen aus hyperphosphoryliertem und aggregiertem Protein Tau. Experimentelle Strategien für eine krankheitsmodifizierende Therapie richten sich deshalb gegen Tau-Protein-vermittelte Toxizität. Sie beinhalten Kinaseinhibitoren, Aggregationshemmer und Substanzen zur Beschleunigung der Tau-Protein-Degradation. Neurofibrillary tangles are the hallmark of Alzheimer's disease together with amyloid plaques. They are composed of hyperphosphorylated and aggregated Tau proteins. Consequently, experimental disease modifying approaches include kinase and aggregation inhibitors as well as substances which increase degradation of Tau proteins

Enhancement of LTP in aged rats is dependent on endogenous BDNF

© 2011 American College of Neuropsychopharmacology.Long-term potentiation (LTP), considered the neurophysiological basis for learning and memory, is facilitated by brain-derived neurotrophic factor (BDNF), an action more evident when LTP is evoked by weak θ-burst stimuli and dependent on co-activation of adenosine A2A receptors (A2AR), which are more expressed in aged rats. As θ-burst stimuli also favor LTP in aged animals, we hypothesized that enhanced LTP in aging could be related to changes in neuromodulation by BDNF. The magnitude of CA1 LTP induced by a weak θ-burst stimuli delivered to the Schaffer collaterals was significantly higher in hippocampal slices taken from 36 to 38 and from 70 to 80-week-old rats, when compared with LTP magnitude in slices from 4 or 10 to 15-week-old rats; this enhancement does not impact in cognitive improvement as aged rats revealed an impairment on hippocampal-dependent learning and memory performance, as assessed by the Morris water maze tests. The scavenger for BDNF, TrkB-Fc, and the inhibitor of Trk phosphorylation, K252a, attenuated LTP in slices from 70 to 80-week-old rats, but not from 10 to 15-week-old rats. When exogenously added, BDNF significantly increased LTP in slices from 4 and 10 to 15-week-old rats, but did not further increased LTP in 36 to 38 or 70 to 80-week-old rats. The effects of exogenous BDNF on LTP were prevented by the A2AR antagonist, SCH58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine). These results indicate that the higher LTP magnitude observed upon aging, which does not translate into improved spatial memory performance, is a consequence of an increase in the tonic action of endogenous BDNF.Fundação para a Ciência e Tecnologia, Fundação Calouste Gulbenkian and EU (COST B-30 concerted action