Mitochondrial Phosphopantetheinylation is Required for Oxidative Function.

Sub-cellular compartmentalization of metabolism has important implications for the local production of metabolites and redox co-factors, as well as pathway regulation. 4'-phosphopantetheinyl (4'PP) groups are essential co-factors derived from coenzyme A and added to target proteins in both the cytoplasm and mitochondria by p hospho p antetheinyl transferase (PPTase) enzymes. Mammals express only one PPTase, thought to localize to the cytoplasm: aminoadipate semialdehyde dehydrogenase phosphopantetheinyl transferase (AASDHPPT); raising the question of how mitochondrial proteins are 4'PP-modified. We found that AASDHPPT is required for mitochondrial respiration and oxidative metabolism via the mitochondrial fatty acid synthesis (mtFAS) pathway. Moreover, we discovered that a pool of AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 13 amino acids of the protein. Our data show that mitochondrial localization of AASDHPPT is required to support mtFAS function, and further identify two variants in Aasdhppt that are likely pathogenic in humans.

Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism.

Contrary to their well-known functions in nutrient breakdown, mitochondria are also important biosynthetic hubs and express an evolutionarily conserved mitochondrial fatty acid synthesis (mtFAS) pathway. mtFAS builds lipoic acid and longer saturated fatty acids, but its exact products, their ultimate destination in cells, and the cellular significance of the pathway are all active research questions. Moreover, why mitochondria need mtFAS despite their well-defined ability to import fatty acids is still unclear. The identification of patients with inborn errors of metabolism in mtFAS genes has sparked fresh research interest in the pathway. New mammalian models have provided insights into how mtFAS coordinates many aspects of oxidative mitochondrial metabolism and raise questions about its role in diseases such as obesity, diabetes, and heart failure. In this review, we discuss the products of mtFAS, their function, and the consequences of mtFAS impairment across models and in metabolic disease.

Amygdala Circuitry During Neurofeedback Training and Symptoms' Change in Adolescents With Varying Depression.

Typical adolescents have increased limbic engagement unchecked by regulatory medial prefrontal cortex (PFC) activity as well as heightened self-focus. The resulting emotion dysregulation and self-focused rumination make adolescents more susceptible to depression and suicide attempts. Heightened self-focus converges with mental illness among depressed adolescents, who deploy exaggerated attention to negative self-relevant stimuli and neglect positive ones as part of depression's phenomenology. This results in rigid negative self-representations during an identity formative period with potential lifetime repercussions. Current empirically supported treatments fail to allay recurrent depression. Evidence-based interventions for illnesses linked to suicide ideation and attempts (e.g., depression) underperform across the lifespan. This could be because current treatments are not successful in altering pervasive negative self-representations and affect dysregulation, which is known to be a risk factor of chronic depression. This study departs from the premise that increasing positive self-processing might be protective against chronic depression particularly during adolescence. The present research is a novel investigation of neurofeedback as a potential treatment alternative for adolescent depression. To enhance positive self-processing, we used the happy self-face as a cue to initiate neurofeedback from the bilateral amygdala and hippocampus and adolescents attempted to upregulate that limbic activity through the recall of positive autobiographical memories. We identified limbic functional circuitry engaged during neurofeedback and links to short-term symptoms' change in depression and rumination. We found that depressed youth showed greater right amygdala to right frontocortical connectivity and lower left amygdala to right frontocortical connectivity compared to healthy controls during neurofeedback vs. control conditions. Depressed youth also showed significant symptom reduction. Connectivity between the right amygdala and frontocortical regions was positively correlated with rumination and depression change, but connectivity between frontocortical regions and the left amygdala was negatively correlated with depression change. The results suggest that depressed youth might engage implicit emotion regulation circuitry while healthy youth recruit explicit emotion regulation circuits during neurofeedback. Our findings support a compensatory approach (i.e., target the right amygdala) during future neurofeedback interventions in depressed youth. Future work ought to include a placebo condition or group.

Neurofeedback and neuroplasticity of visual self-processing in depressed and healthy adolescents: A preliminary study.

Adolescence is a neuroplastic period for self-processing and emotion regulation transformations, that if derailed, are linked to persistent depression. Neural mechanisms of adolescent self-processing and emotion regulation ought to be targeted via new treatments, given moderate effectiveness of current interventions. Thus, we implemented a novel neurofeedback protocol in adolescents to test the engagement of circuits sub-serving self-processing and emotion regulation. METHODS: Depressed (n = 34) and healthy (n = 19) adolescents underwent neurofeedback training using a novel task. They saw their happy face as a cue to recall positive memories and increased displayed amygdala and hippocampus activity. The control condition was counting-backwards while viewing another happy face. A self vs. other face recognition task was administered before and after neurofeedback training. RESULTS: Adolescents showed higher frontotemporal activity during neurofeedback and higher amygdala and hippocampus and hippocampi activity in time series and region of interest analyses respectively. Before neurofeedback there was higher saliency network engagement for self-face recognition, but that network engagement was lower after neurofeedback. Depressed youth exhibited higher fusiform, inferior parietal lobule and cuneus activity during neurofeedback, but controls appeared to increase amygdala and hippocampus activity faster compared to depressed adolescents. CONCLUSIONS: Neurofeedback recruited frontotemporal cortices that support social cognition and emotion regulation. Amygdala and hippocampus engagement via neurofeedback appears to change limbic-frontotemporal networks during self-face recognition. A placebo group or condition and contrasting amygdala and hippocampus, hippocampi or right amygdala versus frontal loci of neurofeedback, e.g. dorsal anterior cingulate cortex, with longer duration of neurofeedback training will elucidate dosage and loci of neurofeedback in adolescents.

Epicardial Conduction Speed, Electrogram Abnormality, and Computed Tomography Attenuation Associations in Arrhythmogenic Right Ventricular Cardiomyopathy.

OBJECTIVES: This study sought to evaluate the association between contrast-enhanced multidetector computed tomography (CE-MDCT) attenuation and local epicardial conduction speed (ECS) and electrographic abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and ventricular tachycardia (VT). BACKGROUND: CE-MDCT is a widely available and fast imaging technology with high spatial resolution that is less prone to defibrillator generator-related safety issues and image artifacts. However, the association between hypoattenuation on MDCT and VT substrates in ARVC remains unknown. METHODS: Patients with ARVC who underwent CE-MDCT followed by endocardial (n = 30) and epicardial (n = 21) electroanatomical mapping (EAM) and VT ablation were prospectively enrolled. Right ventricular (RV) mid-myocardial attenuation was calculated from 3-dimensional MDCT images and registered to EAM. Local ECS was calculated by averaging the ECS between each point and 5 adjacent points with concordant wave front direction. RESULTS: A total of 17,311 epicardial and 5,204 endocardial points were included. In multivariable regression analysis clustered by patient, RV myocardial attenuation was associated with epicardial bipolar voltage amplitude (2.5% decrease in amplitude per 10 HU decrease in attenuation; p < 0.001), with endocardial unipolar voltage amplitude (0.9% decrease in amplitude per 10 HU decrease in attenuation; p < 0.001), and with ECS (0.4% decrease in ECS per 10 HU decrease in attenuation; p = 0.001). CONCLUSIONS: CE-MDCT attenuation distribution is associated with regional ECS and electrographic amplitude in ARVC. Regions with low attenuation likely reflect fibro-fatty involvement in the RV and may serve as important VT substrates in patients with ARVC who are undergoing VT ablation.

Adolescent suicide attempts and ideation are linked to brain function during peer interactions.

Understanding the neural correlates of social interaction among depressed adolescents with suicidal tendencies might help personalize treatment. We tested whether brain function during social interaction is disrupted for depressed adolescents with (1) high suicide ideation and (2) recent attempts. Depressed adolescents with high suicide ideation, including attempters (n = 45;HS) or low suicide ideation (n = 42;LS), and healthy adolescents (n = 39;HC), completed a version of the Cyberball peer interaction task during an fMRI scan. Groups were compared on brain activity during peer exclusion and inclusion versus a non-social condition. During peer exclusion and inclusion, HS youth showed significantly lower activity in precentral and postcentral gyrus, superior temporal gyrus, medial frontal gyrus, insula, and putamen compared to LS youth; and significantly reduced activity in caudate and anterior cingulate cortex compared to HC youth. In a second analysis, suicide attempters (n = 26;SA) were compared to other groups. SA adolescents showed significantly higher activity in ACC and superior and middle frontal gyrus than all other groups. Brain activity was significantly correlated with negative emotionality, social functioning, and cognitive control. Conclusions: Adolescent suicide ideation and attempts were linked to altered neural function during positive and negative peer interactions. We discuss the implications of these findings for suicide prevention efforts.