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The role of mitochondrial dynamics a...

Trudeau, Kyle.

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The role of mitochondrial dynamics and autophagy in pancreatic beta-cell response to nutrient status.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The role of mitochondrial dynamics and autophagy in pancreatic beta-cell response to nutrient status./
作者:	Trudeau, Kyle.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2016,
面頁冊數:	261 p.
附註:	Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.
Contained By:	Dissertation Abstracts International77-10B(E).
標題:	Cellular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10128034
ISBN:	9781339860664

The role of mitochondrial dynamics and autophagy in pancreatic beta-cell response to nutrient status.
Trudeau, Kyle.

The role of mitochondrial dynamics and autophagy in pancreatic beta-cell response to nutrient status. - Ann Arbor : ProQuest Dissertations & Theses, 2016 - 261 p.

Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.

Thesis (Ph.D.)--Boston University, 2016.

This item is not available from ProQuest Dissertations & Theses.

Mitochondrial dynamics includes the processes of fusion, fission, and motility. These processes form interdependent adaptive mechanisms that, together with autophagy, maintain mitochondrial function to meet cellular needs. Mitochondrial dynamics control function directly by inducing bioenergetic remodeling or indirectly by promoting turnover of mitochondria via autophagy. Importantly, mitochondrial dysfunction has been implicated in beta-cell failure during type 2 diabetes. This thesis will investigate the role of dynamics and autophagy in regulating mitochondrial and pancreatic beta-cell function during chronic exposure to excess glucose and fatty acids, termed glucolipotoxicity (GLT).

ISBN: 9781339860664Subjects--Topical Terms:

3172791
Cellular biology.

The role of mitochondrial dynamics and autophagy in pancreatic beta-cell response to nutrient status.
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245 1 4 $a The role of mitochondrial dynamics and autophagy in pancreatic beta-cell response to nutrient status.
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300 $a 261 p.
500 $a Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.
500 $a Adviser: Orian S. Shirihai.
502 $a Thesis (Ph.D.)--Boston University, 2016.
506 $a This item is not available from ProQuest Dissertations & Theses.
520 $a Mitochondrial dynamics includes the processes of fusion, fission, and motility. These processes form interdependent adaptive mechanisms that, together with autophagy, maintain mitochondrial function to meet cellular needs. Mitochondrial dynamics control function directly by inducing bioenergetic remodeling or indirectly by promoting turnover of mitochondria via autophagy. Importantly, mitochondrial dysfunction has been implicated in beta-cell failure during type 2 diabetes. This thesis will investigate the role of dynamics and autophagy in regulating mitochondrial and pancreatic beta-cell function during chronic exposure to excess glucose and fatty acids, termed glucolipotoxicity (GLT).
520 $a It remains ill-defined what role fusion and motility play in determining mitochondrial turnover, as current methodologies to assess turnover lack subcellular resolution. To address this need we developed the use of MitoTimer, a mitochondrial fluorescent probe that undergoes a time-dependent green-to-red transition. Turnover was revealed by the integrated proportions of young (green) and old (red) MitoTimer protein. The results demonstrate that mitochondrial fusion and motility regulate turnover by promoting the distribution of newer protein to subsets of mitochondria in the network. GLT inhibits mitochondrial fusion and networking in pancreatic beta-cells. Since fusion is dependent on motility we tested the hypothesis that GLT impairs fusion by affecting motility. We determined that GLT arrests motility, which may contribute to mitochondrial and beta-cell dysfunction. We show that excess nutrients increase O-linked beta-N-acetyl glucosamine (O-GlcNAc) modification of mitochondrial motor adaptor Milton1, which decreases its activity and results in arrest of motility and increased fission. Thus Milton1 O-GlcNAc modification acts as a nutrient-sensor linking fusion, fission, and motility to nutrient supply in the beta-cell.
520 $a Finally, GLT inhibits autophagic flux with concurrent lysosomal pH increase in beta-cells. To address the hypothesis that impaired lysosomal acidification is a causative event inhibiting autophagic flux and beta-cell function, we developed lysosome-localizing nanoparticles that expand and acidify upon UV photo-activation. Increasing lysosomal acidity with the nanoparticles increased autophagic flux and restored beta-cell function under GLT, establishing lysosomal pH as a key mediator of nutrient-induced beta-cell dysfunction.
520 $a In summary the work elucidates the interdependence and specific roles of mitochondrial fusion, fission, motility, and autophagy in dictating beta-cell responses to excess nutrient environment.
590 $a School code: 0017.
650 4 $a Cellular biology. $3 3172791
650 4 $a Medicine. $3 641104
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710 2 $a Boston University. $b Molecular and Translational Medicine. $3 3285913
773 0 $t Dissertation Abstracts International $g 77-10B(E).
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791 $a Ph.D.
792 $a 2016
793 $a English
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