Nedergaard, Jan (Physiology (Wenner-Gren Institute)) http://su.avedas.com/converis/ws/public/feed/simple/atom/Person/2074/Contract 2013-05-16T02:02:27Z 2013-05-16T02:02:27Z Jan Nedergaard http://su.avedas.com/converis/contract/998 2012-12-18T14:19:25Z 2010-05-22T02:00:49Z

The ageing process is an inescapable part of life, but it is a biological process and must thus have a biologically accessible mechanism. A correlation between accumulated mitochondrial DNA (mtDNA) damage and ageing has long been discussed, but the generation of the mtDNA-mutator mice indicated that increased mtDNA damage at least has the potential to be causative of ageing. However, the link from mtDNA damage to phenotypic ageing is unknown. As the ageing phenotype observed in this model is a consequence of mtDNA damage that should be manifest in the function of the mitochondria, we propose to examine mitochondria from the mtDNA-mutator mice to identify the bioenergetic parameters affected by the damage: respiratory control, efficiency in ATP production, alterations in substrate oxidation capacity, proton leak and respiratory rate as functions of membrane potential, Ca2+ handling, acute superoxide production and cytochrome c release (involved in apoptosis control). The study will be performed in mitochondria from tissues of special interest for the ageing process (brain, muscle, heart, liver, white and brown adipose tissue) and at different time points. The vicious cycle hypothesis of ageing - that reactive oxygen species (ROS) from the mitochondria cause further mitochondrial damage and thus accelerated ROS production - will be open for examination. The investigations will thus elucidate those mitochondrial functions that are most essential for the induced ageing process.

Jan Nedergaard 2010-05-22T02:00:49Z Jan Nedergaard http://su.avedas.com/converis/contract/1000 2012-12-18T14:19:25Z 2010-05-22T02:00:49Z Jan Nedergaard 2010-05-22T02:00:49Z Jan Nedergaard http://su.avedas.com/converis/contract/4081 2013-05-16T02:02:27Z 2011-01-13T02:00:17Z

Thermogenesis is the use of energy with the purpose of only producing heat, a wasteful process that Nature would normally avoid. Nonetheless, through the process of nonshivering thermogenesis mammals have gained evolutionarily. The purpose of this project is to further our understanding of thermogenesis, including so-called diet-induced thermogenesis, a process where energy is apparently combusted only to keep body energy reserves at an optimal level. The tissue supposedly responsible for all nonshivering thermogenesis is brown adipose tissue, through the mitochondrial uncoupling protein UCP1; regulation of its activity will be examined in-vitro and in knock-in mice with mutations in reintroduced UCP1. Microarray analyses of brown versus white adipocytes have shown that brown preadipocytes express myogenic transcription factors, demonstrating that brown adipocytes and muscle constitute a separate lineage from white adipocytes. We will characterize proteins controlling this cellular differentiation. Our recent data indicate the existence of a cell type (*brite* adipocytes) distinct both from classical brown and classical white adipocytes; differentiation regulators of this cell type will also be studied. The studies have current interest in that brown adipose tissue, in addition to being important for survival of small mammals (including human newborns) exposed to cold, is now known to be active in a significant fraction of adult humans and may thus affect energy balance.

Jan Nedergaard 2011-01-13T02:00:17Z