The mitochondrial ADP/ATP carrier (SLC25 family): pathological implications of its dysfunction.

In aerobic eukaryotic cells, the high energy metabolite ATP is generated mainly within the mitochondria following the process of oxidative phosphorylation. The mitochondrial ATP is exported to the cytoplasm using a specialized transport protein, the ADP/ATP carrier, to provide energy to the cell. Any deficiency or dysfunction of this membrane protein leads to serious consequences on cell metabolism and can cause various diseases such as muscular dystrophy. Described as a decisive player in the programmed cell death, it was recently shown to play a role in cancer. The objective of this review is to summarize the current knowledge of the involvement of the ADP/ATP carrier, encoded by the SLC25A4, SLC25A5, SLC25A6 and SLC25A31 genes, in human diseases and of the efforts made at designing different model systems to study this carrier and the associated pathologies through biochemical, genetic, and structural approaches.

An Atypical Mitochondrial Carrier That Mediates Drug Action in Trypanosoma brucei

Elucidating the mechanism of action of trypanocidal compounds is an important step in the development of more efficient drugs against Trypanosoma brucei. In a screening approach using an RNAi library in T. brucei bloodstream forms, we identified a member of the mitochondrial carrier family, TbMCP14, as a prime candidate mediating the action of a group of anti-parasitic choline analogs. Depletion of TbMCP14 by inducible RNAi in both bloodstream and procyclic forms increased resistance of parasites towards the compounds by 7-fold and 3-fold, respectively, compared to uninduced cells. In addition, down-regulation of TbMCP14 protected bloodstream form mitochondria from a drug-induced decrease in mitochondrial membrane potential. Conversely, over-expression of the carrier in procyclic forms increased parasite susceptibility more than 13-fold. Metabolomic analyses of parasites over-expressing TbMCP14 showed increased levels of the proline metabolite, pyrroline-5-carboxylate, suggesting a possible involvement of TbMCP14 in energy production. The generation of TbMCP14 knock-out parasites showed that the carrier is not essential for survival of T. brucei bloodstream forms, but reduced parasite proliferation under standard culture conditions. In contrast, depletion of TbMCP14 in procyclic forms resulted in growth arrest, followed by parasite death. The time point at which parasite proliferation stopped was dependent on the major energy source, i.e. glucose versus proline, in the culture medium. Together with our findings that proline-dependent ATP production in crude mitochondria from TbMCP14-depleted trypanosomes was reduced compared to control mitochondria, the study demonstrates that TbMCP14 is involved in energy production in T. brucei. Since TbMCP14 belongs to a trypanosomatid-specific clade of mitochondrial carrier family proteins showing very poor similarity to mitochondrial carriers of mammals, it may represent an interesting target for drug action or targeting.

Jasmonate-dependent depletion of soluble sugars compromises plant resistance to Manduca sexta

Jasmonates regulate plant secondary metabolism and herbivore resistance. How they influence primary metabolites and how this may affect herbivore growth and performance are not well understood. We profiled sugars and starch of jasmonate biosynthesis-deficient and jasmonate-insensitive Nicotiana attenuata plants and manipulated leaf carbohydrates through genetic engineering and in vitro complementation to assess how jasmonate-dependent sugar accumulation affects the growth of Manduca sexta caterpillars. We found that jasmonates reduce the constitutive and herbivore-induced concentration of glucose and fructose in the leaves across different developmental stages. Diurnal, jasmonate-dependent inhibition of invertase activity was identified as a likely mechanism for this phenomenon. Contrary to our expectation, both in planta and in vitro approaches showed that the lower sugar concentrations led to increased M. sexta growth. As a consequence, jasmonate-dependent depletion of sugars rendered N. attenuata plants more susceptible to M. sexta attack. In conclusion, jasmonates are important regulators of leaf carbohydrate accumulation and this determines herbivore growth. Jasmonate-dependent resistance is reduced rather than enhanced through the suppression of glucose and fructose concentrations, which may contribute to the evolution of divergent resistance strategies of plants in nature.

Molecular Analyses Define Vα7.2-Jα33+ MAIT Cell Depletion in HIV Infection: A Case-Control Study

Mucosal-associated invariant T (MAIT) cells are an abundant antibacterial innate-like lymphocyte population. There are conflicting reports as to their fate in HIV infection. The objective of this study was to determine whether MAIT cells are truly depleted in HIV infection.In this case-control study of HIV-positive patients and healthy controls, quantitative real-time polymerase chain reaction was used to assess the abundance of messenger RNA (mRNA) and genomic DNA (gDNA) encoding the canonical MAIT cell T cell receptor (Vα7.2-Jα33). Comparison was made with flow cytometry.Significant depletion of both Vα7.2-Jα33 mRNA and gDNA was seen in HIV infection. Depletion of Vα7.2+CD161++ T cells was confirmed by flow cytometry. In HIV infection, the abundance of Vα7.2-Jα33 mRNA correlated most strongly with the frequency of Vα7.2+CD161++ cells. No increase was observed in the frequency of Vα7.2+CD161- cells among CD3+CD4- lymphocytes.MAIT cells are depleted from blood in HIV infection as confirmed by independent assays. Significant accumulation of a CD161- MAIT cell population is unlikely. Molecular approaches represent a suitable alternative to flow cytometry-based assays for tracking of MAIT cells in HIV and other settings.

Ego depletion and action initiation

Optimal sprint start performance requires the self-control of responses. Therefore, start performance should depend on self-control strength. It was expected that momentary depletion of self-control strength (ego depletion) would slow down the initiation of a sprint start, resulting in impaired reaction times. N = 37 participants performed three sprint starts at T1 and the average reaction times were measured with a foot-pressure release system attached under the starting block (in ms). Next, participants were randomly assigned to a depletion or a non-depletion condition and self-control strength was experimentally manipulated by applying the transcription task. Following the depletion manipulation, participants performed another series of three sprints (T2). The results of a mixed between (ego depletion: yes vs. no) within (T1 vs. T2) ANOVA supported the hypothesis as average reaction times in the depletion condition significantly increased from T1 (M = 0.35, SD = 0.03) to T2 (M = 0.38, SD = 0.04), F(1, 35) = 6.77, p = .01, η2p = .16. Average reaction times in the non-depletion condition did not differ significantly between T1 (M = 0.36, SD = 0.03) and T2 (M = 0.35, SD = 0.04), F(1, 35) = 0.47, p = .50, η2p = .01. In line with the hypothesis, higher levels of self-control strength were associated with quicker movement initiations. Therefore, improving self-control strength may serve as a buffer against the negative effects of ego depletion on performance.

The effect of ego depletion on distractibility

Athletes in a state of ego depletion do not perform up to their capabilities in high pressure situations (e.g., Englert & Bertrams, 2012). We assume that momentarily available self-control strength determines whether individuals in high pressure situations can resist distracting stimuli. In the present study, we applied a between-subjects design, as 31 experienced basketball players were randomly assigned to a depletion group or a non-depletion group. Participants performed 30 free throws while listening to statements representing worrisome thoughts (as frequently experienced in high pressure situations; Oudejans, Kuijpers, Kooijman, & Bakker, 2011) over stereo headphones. Participants were instructed to block out these distracting audio messages and focus on the free throws. We postulated that depleted participants would be more likely to be distracted and would perform worse in the free throw task. The results supported our assumption as depleted participants paid more attention to the distracting stimuli and displayed worse performance in the free throw task. These results indicate that sufficient levels of self-control strength can serve as a buffer against increased distractibility under pressure. Implementing self-control trainings into workout routines may be a useful approach (e.g., Oaten & Cheng, 2007).

Ego depletion and attention regulation under pressure: Is a temporary loss of self-control strength indeed related to impaired attention regulation?

In the present study we investigated whether ego depletion negatively affects attention regulation under pressure in sports by assessing participants’ dart throwing performance and accompanying gaze behavior. According to the strength model of self-control the most important aspect of self-control is attention regulation (Schmeichel & Baumeister, 2010). As higher levels of state anxiety are associated with impaired attention regulation (Nieuwenhuys & Oudejans, 2012) we chose a mixed design with ego depletion (yes vs. no) as between-subjects and anxiety level (high vs. low) as within-subjects factor. A total of 28 right-handed students participated in our study (Mage = 23.4, SDage = 2.5; 10 female; no professional dart experience). Participants performed a perceptual-motor task requiring selective attention, namely, dart throwing. The task was performed while participants were positioned high and low on a climbing wall (i.e., with high and low levels of anxiety). In line with our expectations, a mixed-design ANOVA revealed that depleted participants in the high anxiety condition performed worse (p < .001) and displayed a shorter final fixation on bull’s eye (p < .01) than in the low anxiety condition, demonstrating that when one is depleted attention regulation under pressure cannot be maintained. This is the first study that directly supports the general assumption that ego depletion is a major factor in influencing attention regulation under pressure.

Depletion of regulatory T cells augments a vaccine-induced T effector cell response against the liver-stage of malaria but fails to increase memory

Regulatory T cells (T(reg)) have been shown to restrict vaccine-induced T cell responses in different experimental models. In these studies CD4(+)CD25(+) T(reg) were depleted using monoclonal antibodies against CD25, which might also interfere with CD25 on non-regulatory T cell populations and would have no effect on Foxp3(+)CD25(-) T(reg). To obtain more insights in the specific function of T(reg) during vaccination we used mice that are transgenic for a bacterial artificial chromosome expressing a diphtheria toxin (DT) receptor-eGFP fusion protein under the control of the foxp3 gene locus (depletion of regulatory T cell mice; DEREG). As an experimental vaccine-carrier recombinant Bordetella adenylate cyclase toxoid fused with a MHC-class I-restricted epitope of the circumsporozoite protein (ACT-CSP) of Plasmodium berghei (Pb) was used. ACT-CSP was shown by us previously to introduce the CD8+ epitope of Pb-CSP into the MHC class I presentation pathway of professional antigen-presenting cells (APC). Using this system we demonstrate here that the number of CSP-specific T cells increases when T(reg) are depleted during prime but also during boost immunization. Importantly, despite this increase of T effector cells no difference in the number of antigen-specific memory cells was observed.

Choking under Pressure und Ego Depletion: Eine Erweiterung der Attentional Control Theory und mögliche Interventionsmaßnahmen

In Leistungssituationen sind Athletinnen und Athleten nicht immer dazu in der Lage, ihr Leistungsoptimum abzurufen. Auch wenn die Befundlage zum Angst-Leistungszusammenhang äußerst heterogen ist, so geht höheres Angsterleben häufig mit Leistungsbeeinträchtigungen einher. In dem vorliegenden Manuskript wird ein Überblick über verschiedene theoretische Modelle zur Erklärung des Angst-Leistungszusammenhangs gegeben. Der Fokus wird dabei auf die Attentional Control Theory gelegt, die besagt, dass unter Druck die Aufmerksamkeitsregulation weniger effizient ausfällt und folglich erhöhte Ablenkbarkeit die Leistung negativ beeinflusst. Es wird weiterhin argumentiert, dass die Selbstkontrollkraft den Angst-Leistungszusammenhang moderiert, so dass nur bei Personen mit temporär erschöpfter Selbstkontrollkraft ein negativer Angst-Leistungszusammenhang erwartet wird, wohingegen Personen mit momentan verfügbarer Selbstkontrollkraft trotz erhöhten Angsterlebens Höchstleistung erbringen können. Abschließend werden offene Fragestellungen thematisiert, alternative Erklärungsansätze vorgestellt sowie praktische Implikationen für die Sportpsychologie abgeleitet.

The influence of ego depletion on sprint start performance in athletes without track and field experience

We tested the assumption that ego depletion would affect the sprint start in a sample of N = 38 athletes without track and field experience in an experiment by applying a mixed between- (depletion vs. non-depletion) within- (T1: before manipulation of ego depletion vs. T2: after manipulation of ego depletion) subjects design. We assumed that ego depletion would increase the possibility for a false start, as regulating the impulse to initiate the sprinting movement too soon before the starting signal requires self-control. In line with our assumption, we found a significant interaction as there was only a significant increase in the number of false starts from T1 to T2 for the depletion group while this was not the case for the non-depletion group. We conclude that ego depletion has a detrimental influence on the sprint start in athletes without track and field experience.