Desjardins 2022 Proc Natl Acad Sci U S A

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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 AMPKΞ²1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids.

Β» Proc Natl Acad Sci U S A 119:e2119824119. PMID: 36409897 Open Access

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 (2022) Proc Natl Acad Sci U S A

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 Ξ²1 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 AMPKΞ²1 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 AMPKΞ²1 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. β€’ Keywords: AMPK, NAFLD, Autophagy, Fat oxidation, Mitochondria β€’ Bioblast editor: Plangger M

Labels: MiParea: Respiration, Genetic knockout;overexpression 

Organism: Mouse  Tissue;cell: Liver  Preparation: Isolated mitochondria 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, NS  HRR: Oxygraph-2k 


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