BNIP3-dependent mitophagy promotes cytosolic localization of LC3B and metabolic homeostasis in the liver
Mitophagy formed the basis of the original description of autophagy by Christian de Duve when he demonstrated that GCG (glucagon) induced macroautophagic/autophagic turnover of mitochondria in the liver. However, the molecular basis of liver-specific activation of mitophagy by GCG, or its significance for metabolic stress responses in the liver is not understood. Here we show that BNIP3 is required for GCG-induced mitophagy in the liver through interaction with processed LC3B; an interaction that is also necessary to localize LC3B out of the nucleus to cytosolic mitophagosomes in response to nutrient deprivation. Loss of BNIP3-dependent mitophagy caused excess mitochondria to accumulate in the liver, disrupting metabolic zonation within the liver parenchyma, with expansion of zone 1 metabolism at the expense of zone 3 metabolism. These results identify BNIP3 as a regulator of metabolic homeostasis in the liver through its effect on mitophagy and mitochondrial mass distribution.Abbreviations: ASS1, arginosuccinate synthetase; BNIP3, BCL2/adenovirus E1B interacting protein 3; CV, central vein; GCG - glucagon; GLUL, glutamate- ammonia ligase (glutamine synthetase); HCQ, hydroxychloroquine; LIR, LC3-interacting region; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 beta; mtDNA:nucDNA, ratio of mitochondrial DNA to nuclear DNA; PV, periportal vein; TOMM20, translocase of outer mitochondrial membrane protein 20.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
Autophagy - 17(2021), 11 vom: 01. Nov., Seite 3530-3546 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Springer, Maya Z [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.03.2022 Date Revised 24.03.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1080/15548627.2021.1877469 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM320217493 |
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| 100 | 1 | |a Springer, Maya Z |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a BNIP3-dependent mitophagy promotes cytosolic localization of LC3B and metabolic homeostasis in the liver |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 24.03.2022 | ||
| 500 | |a Date Revised 24.03.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Mitophagy formed the basis of the original description of autophagy by Christian de Duve when he demonstrated that GCG (glucagon) induced macroautophagic/autophagic turnover of mitochondria in the liver. However, the molecular basis of liver-specific activation of mitophagy by GCG, or its significance for metabolic stress responses in the liver is not understood. Here we show that BNIP3 is required for GCG-induced mitophagy in the liver through interaction with processed LC3B; an interaction that is also necessary to localize LC3B out of the nucleus to cytosolic mitophagosomes in response to nutrient deprivation. Loss of BNIP3-dependent mitophagy caused excess mitochondria to accumulate in the liver, disrupting metabolic zonation within the liver parenchyma, with expansion of zone 1 metabolism at the expense of zone 3 metabolism. These results identify BNIP3 as a regulator of metabolic homeostasis in the liver through its effect on mitophagy and mitochondrial mass distribution.Abbreviations: ASS1, arginosuccinate synthetase; BNIP3, BCL2/adenovirus E1B interacting protein 3; CV, central vein; GCG - glucagon; GLUL, glutamate- ammonia ligase (glutamine synthetase); HCQ, hydroxychloroquine; LIR, LC3-interacting region; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 beta; mtDNA:nucDNA, ratio of mitochondrial DNA to nuclear DNA; PV, periportal vein; TOMM20, translocase of outer mitochondrial membrane protein 20 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a BNIP3 | |
| 650 | 4 | |a LC3B | |
| 650 | 4 | |a glucagon | |
| 650 | 4 | |a hepatocyte | |
| 650 | 4 | |a liver zonation | |
| 650 | 4 | |a mitophagy | |
| 650 | 4 | |a nutrient deprivation | |
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| 650 | 7 | |a BNip3 protein, mouse |2 NLM | |
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| 650 | 7 | |a Map1lc3b protein, mouse |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a Microtubule-Associated Proteins |2 NLM | |
| 650 | 7 | |a Mitochondrial Proteins |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins |2 NLM | |
| 650 | 7 | |a RNA, Messenger |2 NLM | |
| 650 | 7 | |a Glucagon |2 NLM | |
| 650 | 7 | |a 9007-92-5 |2 NLM | |
| 700 | 1 | |a Poole, Logan P |e verfasserin |4 aut | |
| 700 | 1 | |a Drake, Lauren E |e verfasserin |4 aut | |
| 700 | 1 | |a Bock-Hughes, Althea |e verfasserin |4 aut | |
| 700 | 1 | |a Boland, Michelle L |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Alexandra G |e verfasserin |4 aut | |
| 700 | 1 | |a Hart, John |e verfasserin |4 aut | |
| 700 | 1 | |a Chourasia, Aparajita H |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Ivan |e verfasserin |4 aut | |
| 700 | 1 | |a Bozek, Grazyna |e verfasserin |4 aut | |
| 700 | 1 | |a Macleod, Kay F |e verfasserin |4 aut | |
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