edoc

Metabolic consequences of neuronal mitochondrial fission ablation

Restelli, Lisa Michelle. Metabolic consequences of neuronal mitochondrial fission ablation. 2016, PhD Thesis, University of Basel, Faculty of Science.

[img]
Preview
PDF
48Mb

Official URL: http://edoc.unibas.ch/diss/DissB_11746

Downloads: Statistics Overview

Abstract

Dynamin-related protein 1 (Drp1), the main mammalian mediator of mitochondrial fission, has an especially important role in neuronal development, such that its deletion gives rise to pre- or perinatal lethality. However, less is known about the need for Drp1 in adult neurons; this is relevant because inhibition of Drp1 could prevent pre-apoptotic mitochondrial fragmentation, and therefore be neuroprotective.
In our mouse model, inducible Drp1 ablation in the forebrain of adult mice leads to swollen, perinuclearly aggregated mitochondria and to impaired synaptic transmission. Of note, ablated mice also develop a complex and ultimately lethal catabolic phenotype, marked by weight loss, increased lipolysis and elevated corticosterone. We traced this back to the activation of the integrated stress response in Drp1-ablated brain regions, culminating in the ectopic induction of metabolic cytokine Fgf21. Fgf21 is normally produced in liver, fat and muscle tissue in response to fasting or exercise, and no reports exist of it being produced in the brain. This “mitokine” increases insulin sensitivity and stimulates corticosterone production via receptors in the hypothalamus, thus explaining essential aspects of the catabolic phenotype.
This work has implications not only for mitochondrial biology but also for the understanding of the central regulation of systemic metabolism.
Advisors:Handschin, Christoph and Frank, Stephan and Spang, Anne
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Growth & Development (Handschin)
Item Type:Thesis
Thesis no:11746
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (XV, 174 Seiten)
Language:English
Identification Number:
Last Modified:02 Sep 2016 08:54
Deposited On:02 Sep 2016 08:53

Repository Staff Only: item control page