Mitochondria constantly undergo fusion and fission events, referred as mitochondrial dynamics, which determine mitochondrial architecture and bioenergetics. Cultured cell studies demonstrate that ...mitochondrial dynamics are acutely regulated by phosphorylation of the mitochondrial fission orchestrator dynamin-related protein 1 (Drp1) at S579 or S600. However, the physiological impact and crosstalk of these phosphorylation sites is poorly understood. Here, we describe the functional interrelation between S579 and S600 phosphorylation sites in vivo and their role on mitochondrial remodeling. Mice carrying a homozygous Drp1 S600A knockin (Drp1 KI) mutation display larger mitochondria and enhanced lipid oxidation and respiratory capacities, granting improved glucose tolerance and thermogenic response upon high-fat feeding. Housing mice at thermoneutrality blunts these differences, suggesting a role for the brown adipose tissue in the protection of Drp1 KI mice against metabolic damage. Overall, we demonstrate crosstalk between Drp1 phosphorylation sites and provide evidence that their modulation could be used in the treatment and prevention of metabolic diseases.
Display omitted
•Drp1 phosphorylation at S600 promotes the phosphorylation at the S579 site•Both Drp1 P-S600 and P-S579 are required for maximal mitochondrial fragmentation•Drp1 S600A knockin mice are protected against diet-induced metabolic damage•Drp1 phosphorylation controls brown adipose tissue thermogenic capacity in mice
Valera-Alberni et al. show that in mouse cells and tissues, Drp1 phosphorylation at S600 prompts the downstream phosphorylation of S579, triggering mitochondrial fission. Accordingly, Drp1 S600A knockin (Drp1 KI) mice display enlarged mitochondria. Metabolically, Drp1 KI mice show increased lipid oxidation capacity and are protected against diet-induced metabolic disease.
Background and Purpose- Genome-wide association studies have identified the
(histone deacetylase 9) gene region as a major risk locus for atherosclerotic stroke and coronary artery disease in humans. ...Previous results suggest a role of altered
expression levels as the underlying disease mechanism. rs2107595, the lead single nucleotide polymorphism for stroke and coronary artery disease resides in noncoding DNA and colocalizes with histone modification marks suggestive of enhancer elements. Methods- To determine the mechanisms by which genetic variation at rs2107595 regulates
expression and thus vascular risk we employed targeted resequencing, proteome-wide search for allele-specific nuclear binding partners, chromatin immunoprecipitation, genome-editing, reporter assays, circularized chromosome conformation capture, and gain- and loss-of-function experiments in cultured human cell lines and primary immune cells. Results- Targeted resequencing of the
locus in patients with atherosclerotic stroke and controls supported candidacy of rs2107595 as the causative single nucleotide polymorphism. A proteomic search for nuclear binding partners revealed preferential binding of the E2F3/TFDP1/Rb1 complex (E2F transcription factor 3/transcription factor Dp-1/Retinoblastoma 1) to the rs2107595 common allele, consistent with the disruption of an E2F3 consensus site by the risk allele. Gain- and loss-of-function studies showed a regulatory effect of E2F/Rb proteins on
expression. Compared with the common allele, the rs2107595 risk allele exhibited higher transcriptional capacity in luciferase assays and was associated with higher
mRNA levels in primary macrophages and genome-edited Jurkat cells. Circularized chromosome conformation capture revealed a genomic interaction of the rs2107595 region with the
promoter, which was stronger for the common allele as was the in vivo interaction with E2F3 and Rb1 determined by chromatin immunoprecipitation. Gain-of-function experiments in isogenic Jurkat cells demonstrated a key role of E2F3 in mediating rs2107595-dependent transcriptional regulation of
. Conclusions- Collectively, our findings imply allele-specific transcriptional regulation of
via E2F3 and Rb1 as a major mechanism mediating vascular risk at rs2107595.
Alexa, Can You Help Us Solve This Problem? Winkler, Rainer; Söllner, Matthias; Neuweiler, Maya Lisa ...
Extended Abstracts of the 2019 CHI Conference on Human Factors in Computing Systems,
05/2019
Conference Proceeding
Despite a growing body of research about the design and use of Smart Personal Assistants, existing work has mainly focused on their use as task support for individual users in rather simple problem ...scenarios. Less is known about their ability to improve collaboration among multiple users in more complex problem settings. In our study, we directly compare 21 groups who either use a Smart Personal Assistant tutor or a human tutor when solving a problem task. The results indicate that groups interacting with Smart Personal Assistant tutors show significantly higher task outcomes and higher degrees of collaboration quality compared to groups interacting with human tutors. The results are used to suggest areas for future research in the field of computer-supported collaboration.
PDF
