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Mitochondria Lipid-Droplet Interaction in the Control of Cellular Lipid Metabolism.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Mitochondria Lipid-Droplet Interaction in the Control of Cellular Lipid Metabolism./
作者:	Brownstein, Alexandra.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2023,
面頁冊數:	165 p.
附註:	Source: Dissertations Abstracts International, Volume: 85-03, Section: B.
Contained By:	Dissertations Abstracts International85-03B.
標題:	Endocrinology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30639720
ISBN:	9798380364201

Mitochondria Lipid-Droplet Interaction in the Control of Cellular Lipid Metabolism.
Brownstein, Alexandra.

Mitochondria Lipid-Droplet Interaction in the Control of Cellular Lipid Metabolism. - Ann Arbor : ProQuest Dissertations & Theses, 2023 - 165 p.

Source: Dissertations Abstracts International, Volume: 85-03, Section: B.

Thesis (Ph.D.)--University of California, Los Angeles, 2023.

An imbalance in energy homeostasis leads to increased lipid storage and obesity. Mechanisms that regulate cellular lipid storage or utilization are thought to play a key role in maintaining energy balance and overall metabolic health. However the mechanisms that regulate energy expenditure and fuel utilization are not well understood. Here we address these gaps in knowledge by first describing a novel mechanism to increase energy expenditure by regulating mitochondrial fuel utilization. We find that blocking pyruvate entry into the mitochondria increases energy expenditure by activating an ATP-demanding lipid cycle of LD breakdown and buildup that is fueled by lipid oxidation. Moreover, recent studies have demonstrated heterogeneity in mitochondrial function, and identified a unique population of BAT mitochondria that support lipid storage by anchoring themselves to LD and facilitating TG synthesis and LD expansion. However, it remains unknown if these unique mitochondria are conserved in other tissues. Here, I describe the development of the first approach to isolate PDM from WAT. Using this approach I show that PDM in WAT have a unique function that is distinct from BAT. Future research understanding the mechanisms that control subpopulations of mitochondria and their roles in lipid homeostasis can provide novel methods of altering energy metabolism through mitochondria.ATP-consuming futile cycles as energy dissipating mechanisms to counteract obesityObesity results from an imbalance in energy homeostasis, whereby excessive energy intake exceeds caloric expenditure. Energy can be dissipated out of an organism by producing heat (thermogenesis), explaining the long-standing interest in exploiting thermogenic processes to counteract obesity. Mitochondrial uncoupling is a process that expends energy by oxidizing nutrients to produce heat, instead of ATP synthesis. Energy can also be dissipated through mechanisms that do not involve mitochondrial uncoupling. Such mechanisms include futile cycles described as metabolic reactions that consume ATP to produce a product from a substrate but then converting the product back into the original substrate, releasing the energy as heat. Energy dissipation driven by cellular ATP demand can be regulated by adjusting the speed and number of futile cycles. Energy consuming futile cycles that are reviewed here are lipolysis/fatty acid re-esterification cycle, creatine/phosphocreatine cycle, and the SERCA-mediated calcium import and export cycle. Their reliance on ATP emphasizes that mitochondrial oxidative function coupled to ATP synthesis, and not just uncoupling, can play a role in thermogenic energy dissipation. Here, we review ATP consuming futile cycles, the evidence for their function in humans, and their potential employment as a strategy to dissipate energy and counteract obesity.Mitochondria isolated from lipid droplets in WAT reveal functional differences based on lipid droplet sizeRecent studies in brown adipose tissue (BAT) described a unique subpopulation of mitochondria bound to lipid droplets (LDs), peridroplet mitochondria (PDM). PDMs can be isolated from BAT by simple differential centrifugation and salt washes. These protocols have so far not led to successful isolation of PDMs from WAT, which seem to show stronger binding to LD than in BAT. Here, we developed a method to isolate PDM from WAT with high yield and purity by an optimized proteolytic treatment that preserves the respiratory function of mitochondria intact. Using this approach, we show that, contrary to BAT, WAT PDM have lower respiratory and ATP synthesis capacity compared to WAT CM. Furthermore, by isolating PDM from fractions containing LDs of different sizes, we find a negative correlation between LD size and the respiratory capacity of their PDM in WAT. Thus, our new isolation method reveals tissue-specific characteristics of PDM and establishes the existence of heterogeneity in PDM function determined by LD size.

ISBN: 9798380364201Subjects--Topical Terms:

610914
Endocrinology.
Subjects--Index Terms:

Energy homeostasis

Mitochondria Lipid-Droplet Interaction in the Control of Cellular Lipid Metabolism.
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502 $a Thesis (Ph.D.)--University of California, Los Angeles, 2023.
520 $a An imbalance in energy homeostasis leads to increased lipid storage and obesity. Mechanisms that regulate cellular lipid storage or utilization are thought to play a key role in maintaining energy balance and overall metabolic health. However the mechanisms that regulate energy expenditure and fuel utilization are not well understood. Here we address these gaps in knowledge by first describing a novel mechanism to increase energy expenditure by regulating mitochondrial fuel utilization. We find that blocking pyruvate entry into the mitochondria increases energy expenditure by activating an ATP-demanding lipid cycle of LD breakdown and buildup that is fueled by lipid oxidation. Moreover, recent studies have demonstrated heterogeneity in mitochondrial function, and identified a unique population of BAT mitochondria that support lipid storage by anchoring themselves to LD and facilitating TG synthesis and LD expansion. However, it remains unknown if these unique mitochondria are conserved in other tissues. Here, I describe the development of the first approach to isolate PDM from WAT. Using this approach I show that PDM in WAT have a unique function that is distinct from BAT. Future research understanding the mechanisms that control subpopulations of mitochondria and their roles in lipid homeostasis can provide novel methods of altering energy metabolism through mitochondria.ATP-consuming futile cycles as energy dissipating mechanisms to counteract obesityObesity results from an imbalance in energy homeostasis, whereby excessive energy intake exceeds caloric expenditure. Energy can be dissipated out of an organism by producing heat (thermogenesis), explaining the long-standing interest in exploiting thermogenic processes to counteract obesity. Mitochondrial uncoupling is a process that expends energy by oxidizing nutrients to produce heat, instead of ATP synthesis. Energy can also be dissipated through mechanisms that do not involve mitochondrial uncoupling. Such mechanisms include futile cycles described as metabolic reactions that consume ATP to produce a product from a substrate but then converting the product back into the original substrate, releasing the energy as heat. Energy dissipation driven by cellular ATP demand can be regulated by adjusting the speed and number of futile cycles. Energy consuming futile cycles that are reviewed here are lipolysis/fatty acid re-esterification cycle, creatine/phosphocreatine cycle, and the SERCA-mediated calcium import and export cycle. Their reliance on ATP emphasizes that mitochondrial oxidative function coupled to ATP synthesis, and not just uncoupling, can play a role in thermogenic energy dissipation. Here, we review ATP consuming futile cycles, the evidence for their function in humans, and their potential employment as a strategy to dissipate energy and counteract obesity.Mitochondria isolated from lipid droplets in WAT reveal functional differences based on lipid droplet sizeRecent studies in brown adipose tissue (BAT) described a unique subpopulation of mitochondria bound to lipid droplets (LDs), peridroplet mitochondria (PDM). PDMs can be isolated from BAT by simple differential centrifugation and salt washes. These protocols have so far not led to successful isolation of PDMs from WAT, which seem to show stronger binding to LD than in BAT. Here, we developed a method to isolate PDM from WAT with high yield and purity by an optimized proteolytic treatment that preserves the respiratory function of mitochondria intact. Using this approach, we show that, contrary to BAT, WAT PDM have lower respiratory and ATP synthesis capacity compared to WAT CM. Furthermore, by isolating PDM from fractions containing LDs of different sizes, we find a negative correlation between LD size and the respiratory capacity of their PDM in WAT. Thus, our new isolation method reveals tissue-specific characteristics of PDM and establishes the existence of heterogeneity in PDM function determined by LD size.
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650 4 $a Endocrinology. $3 610914
650 4 $a Cellular biology. $3 3172791
650 4 $a Molecular biology. $3 517296
653 $a Energy homeostasis
653 $a Lipid storage
653 $a Obesity
653 $a Lipid oxidation
653 $a Lipid droplets
653 $a Brown adipose tissue
653 $a Peridroplet mitochondria
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690 $a 0379
690 $a 0307
710 2 $a University of California, Los Angeles. $b Molec, Cell, & Integ Physiology 0568. $3 3181612
773 0 $t Dissertations Abstracts International $g 85-03B.
790 $a 0031
791 $a Ph.D.
792 $a 2023
793 $a English
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