The phosphorylation of AMPKβ1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids

Research output: Contribution to journal › Journal article › Research › peer-review

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The phosphorylation of AMPKβ1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids. / Desjardins, Eric M.; Smith, Brennan K.; Day, Emily A.; Ducommun, Serge; Sanders, Matthew J.; Nederveen, Joshua P.; Ford, Rebecca J.; Pinkosky, Stephen L.; Townsend, Logan K.; Gutgesell, Robert M.; Lu, Rachel; Sakamoto, Kei; Steinberg, Gregory R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 119, No. 48, e2119824119, 2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Desjardins, EM, Smith, BK, Day, EA, Ducommun, S, Sanders, MJ, Nederveen, JP, Ford, RJ, Pinkosky, SL, Townsend, LK, Gutgesell, RM, Lu, R, Sakamoto, K & Steinberg, GR 2022, 'The phosphorylation of AMPKβ1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids', Proceedings of the National Academy of Sciences of the United States of America, vol. 119, no. 48, e2119824119. https://doi.org/10.1073/pnas.2119824119

APA

Desjardins, E. M., Smith, B. K., Day, E. A., Ducommun, S., Sanders, M. J., Nederveen, J. P., Ford, R. J., Pinkosky, S. L., Townsend, L. K., Gutgesell, R. M., Lu, R., Sakamoto, K., & Steinberg, G. R. (2022). The phosphorylation of AMPKβ1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids. Proceedings of the National Academy of Sciences of the United States of America, 119(48), [e2119824119]. https://doi.org/10.1073/pnas.2119824119

Vancouver

Desjardins EM, Smith BK, Day EA, Ducommun S, Sanders MJ, Nederveen JP et al. The phosphorylation of AMPKβ1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids. Proceedings of the National Academy of Sciences of the United States of America. 2022;119(48). e2119824119. https://doi.org/10.1073/pnas.2119824119

Author

Desjardins, Eric M. ; Smith, Brennan K. ; Day, Emily A. ; Ducommun, Serge ; Sanders, Matthew J. ; Nederveen, Joshua P. ; Ford, Rebecca J. ; Pinkosky, Stephen L. ; Townsend, Logan K. ; Gutgesell, Robert M. ; Lu, Rachel ; Sakamoto, Kei ; Steinberg, Gregory R. / The phosphorylation of AMPKβ1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids. In: Proceedings of the National Academy of Sciences of the United States of America. 2022 ; Vol. 119, No. 48.

Bibtex

@article{d9908c83ba414ed38fe9e30a9eab587e,
title = "The phosphorylation of AMPKβ1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids",
abstract = "Fatty acids are vital for the survival of eukaryotes, but when present in excess can have deleterious consequences. The AMP-activated protein kinase (AMPK) is an important regulator of multiple branches of metabolism. Studies in purified enzyme preparations and cultured cells have shown that AMPK is allosterically activated by small molecules as well as fatty acyl-CoAs through a mechanism involving Ser108 within the regulatory AMPK β1 isoform. However, the in vivo physiological significance of this residue has not been evaluated. In the current study, we generated mice with a targeted germline knock-in (KI) mutation of AMPKβ1 Ser108 to Ala (S108A-KI), which renders the site phospho-deficient. S108A-KI mice had reduced AMPK activity (50 to 75%) in the liver but not in the skeletal muscle. On a chow diet, S108A-KI mice had impairments in exogenous lipid-induced fatty acid oxidation. Studies in mice fed a high-fat diet found that S108A-KI mice had a tendency for greater glucose intolerance and elevated liver triglycerides. Consistent with increased liver triglycerides, livers of S108A-KI mice had reductions in mitochondrial content and respiration that were accompanied by enlarged mitochondria, suggestive of impairments in mitophagy. Subsequent studies in primary hepatocytes found that S108A-KI mice had reductions in palmitate- stimulated Cpt1a and Ppargc1a mRNA, ULK1 phosphorylation and autophagic/mitophagic flux. These data demonstrate an important physiological role of AMPKβ1 Ser108 phosphorylation in promoting fatty acid oxidation, mitochondrial biogenesis and autophagy under conditions of high lipid availability. As both ketogenic diets and intermittent fasting increase circulating free fatty acid levels, AMPK activity, mitochondrial biogenesis, and mitophagy, these data suggest a potential unifying mechanism which may be important in mediating these effects.",
keywords = "AMPK, autophagy, fat oxidation, mitochondria, NAFLD",
author = "Desjardins, {Eric M.} and Smith, {Brennan K.} and Day, {Emily A.} and Serge Ducommun and Sanders, {Matthew J.} and Nederveen, {Joshua P.} and Ford, {Rebecca J.} and Pinkosky, {Stephen L.} and Townsend, {Logan K.} and Gutgesell, {Robert M.} and Rachel Lu and Kei Sakamoto and Steinberg, {Gregory R.}",
year = "2022",
doi = "10.1073/pnas.2119824119",
language = "English",
volume = "119",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "48",

}

RIS

TY - JOUR

T1 - The phosphorylation of AMPKβ1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids

AU - Desjardins, Eric M.

AU - Smith, Brennan K.

AU - Day, Emily A.

AU - Ducommun, Serge

AU - Sanders, Matthew J.

AU - Nederveen, Joshua P.

AU - Ford, Rebecca J.

AU - Pinkosky, Stephen L.

AU - Townsend, Logan K.

AU - Gutgesell, Robert M.

AU - Lu, Rachel

AU - Sakamoto, Kei

AU - Steinberg, Gregory R.

PY - 2022

Y1 - 2022

N2 - Fatty acids are vital for the survival of eukaryotes, but when present in excess can have deleterious consequences. The AMP-activated protein kinase (AMPK) is an important regulator of multiple branches of metabolism. Studies in purified enzyme preparations and cultured cells have shown that AMPK is allosterically activated by small molecules as well as fatty acyl-CoAs through a mechanism involving Ser108 within the regulatory AMPK β1 isoform. However, the in vivo physiological significance of this residue has not been evaluated. In the current study, we generated mice with a targeted germline knock-in (KI) mutation of AMPKβ1 Ser108 to Ala (S108A-KI), which renders the site phospho-deficient. S108A-KI mice had reduced AMPK activity (50 to 75%) in the liver but not in the skeletal muscle. On a chow diet, S108A-KI mice had impairments in exogenous lipid-induced fatty acid oxidation. Studies in mice fed a high-fat diet found that S108A-KI mice had a tendency for greater glucose intolerance and elevated liver triglycerides. Consistent with increased liver triglycerides, livers of S108A-KI mice had reductions in mitochondrial content and respiration that were accompanied by enlarged mitochondria, suggestive of impairments in mitophagy. Subsequent studies in primary hepatocytes found that S108A-KI mice had reductions in palmitate- stimulated Cpt1a and Ppargc1a mRNA, ULK1 phosphorylation and autophagic/mitophagic flux. These data demonstrate an important physiological role of AMPKβ1 Ser108 phosphorylation in promoting fatty acid oxidation, mitochondrial biogenesis and autophagy under conditions of high lipid availability. As both ketogenic diets and intermittent fasting increase circulating free fatty acid levels, AMPK activity, mitochondrial biogenesis, and mitophagy, these data suggest a potential unifying mechanism which may be important in mediating these effects.

AB - Fatty acids are vital for the survival of eukaryotes, but when present in excess can have deleterious consequences. The AMP-activated protein kinase (AMPK) is an important regulator of multiple branches of metabolism. Studies in purified enzyme preparations and cultured cells have shown that AMPK is allosterically activated by small molecules as well as fatty acyl-CoAs through a mechanism involving Ser108 within the regulatory AMPK β1 isoform. However, the in vivo physiological significance of this residue has not been evaluated. In the current study, we generated mice with a targeted germline knock-in (KI) mutation of AMPKβ1 Ser108 to Ala (S108A-KI), which renders the site phospho-deficient. S108A-KI mice had reduced AMPK activity (50 to 75%) in the liver but not in the skeletal muscle. On a chow diet, S108A-KI mice had impairments in exogenous lipid-induced fatty acid oxidation. Studies in mice fed a high-fat diet found that S108A-KI mice had a tendency for greater glucose intolerance and elevated liver triglycerides. Consistent with increased liver triglycerides, livers of S108A-KI mice had reductions in mitochondrial content and respiration that were accompanied by enlarged mitochondria, suggestive of impairments in mitophagy. Subsequent studies in primary hepatocytes found that S108A-KI mice had reductions in palmitate- stimulated Cpt1a and Ppargc1a mRNA, ULK1 phosphorylation and autophagic/mitophagic flux. These data demonstrate an important physiological role of AMPKβ1 Ser108 phosphorylation in promoting fatty acid oxidation, mitochondrial biogenesis and autophagy under conditions of high lipid availability. As both ketogenic diets and intermittent fasting increase circulating free fatty acid levels, AMPK activity, mitochondrial biogenesis, and mitophagy, these data suggest a potential unifying mechanism which may be important in mediating these effects.

KW - AMPK

KW - autophagy

KW - fat oxidation

KW - mitochondria

KW - NAFLD

U2 - 10.1073/pnas.2119824119

DO - 10.1073/pnas.2119824119

M3 - Journal article

C2 - 36409897

AN - SCOPUS:85142349793

VL - 119

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 48

M1 - e2119824119

ER -

ID: 327321577