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Mitochondria-Lipid-droplet interaction: Where Mitochondrial Dynamics Meet Bioenergetics
Biochimica et Biophysica Acta - Bioenergetics ; Conference: EBEC2022, 2022.
Article in English | EMBASE | ID: covidwho-2176720
ABSTRACT
Mitochondria surrounding lipid droplets (Peri-Droplet Mitochondria;PDM) maintain a unique proteome which is not equilibrated with the rest of the mitochondrial population. We find that PDM remain stationary and elongated on lipid droplets, fuel lipid droplet expansion, and do not fuse with cytosolic mitochondria. Compared to cytosolic mitochondria, PDM have higher capacity to metabolize pyruvate but reduced capacity to oxidize fatty acids. We reveal for the first time the mechanism by which the elongated mitochondrial shape of PDM differentiate their fuel preference from that of cytosolic mitochondria. We find that mitochondrial elongation reduces fatty acid utilization by inhibiting CPT1 activity. On the other hand, we find that mitochondrial fragmentation, such as observed in NASH, increases mitochondrial lipid utilization and may act as a compensatory mechanism to reduce lipotoxicity. Indeed, inhibition of fission in a model of NASH exacerbated NASH phenotype. We developed a cell-based imaging for the quantification of mitochondria-lipid droplet association and identified a set of small molecules that detach mitochondria from lipid droplets (PDM-Detachers). New unpublished data demonstrate PDM detachers induce lipolysis and lipid droplet shrinkage. Using these tools we assessed the role of lipid droplets in SARS-CoV2 expansion. We find that proliferation of various coronaviruses can be strongly inhibited by PDM-detachers and enhanced by attaching mitochondria to lipid droplets. We demonstrate that PDM can be found in humans. We studied adipose tissue from pheochromocytoma patients, a model of white adipose browning characterized by enhanced capacity for energy expenditure. Remarkably, bioenergetic changes associated with browning were primarily localized to PDM. Similar changes were found in a mouse model of re-browning, where PDM increased in whitened brown adipose tissue upon reducing housing temperature. Copyright © 2022
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Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Biochimica et Biophysica Acta - Bioenergetics Year: 2022 Document Type: Article

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Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Biochimica et Biophysica Acta - Bioenergetics Year: 2022 Document Type: Article