Search
Search articles by title, abstract,author or doi
Advanced search

AMPK integrates energy and material metabolism

Yun-Zi Mao , Shi-Min Zhao

Vita ››

PDF (329KB)
Vita > Cutting Edge > DOI: 10.15302/vita.2026.08.0069
Vita Open AccessPublished:

AMPK integrates energy and material metabolism

Author information +
History +
Vita () Cite this article
PDF (329KB)

AMP-activated protein kinase (AMPK) has classically been viewed as a sensor of cellular energy deficit. Reporting in Vita, Wang et al. show that LKB1 directly senses several glycolytic metabolites to control AMPK activity, which, together with previous reports that AMPK is regulated by other intermediary metabolites, positions AMPK as a metabolic pivot beyond energy-charge sensing.

登录浏览全文

4963

注册一个新账户 忘记密码

In the canonical model, AMPK is a conserved heterotrimeric complex that maintains energy balance by stimulating ATP-producing pathways while restraining ATP-consuming biosynthesis1. An increase in AMP relative to ATP is sensed by the AMPKγ subunit. AMP binding allosterically activates AMPK and promotes phosphorylation of the catalytic α subunit at Thr172, principally by the upstream LKB1–STRAD–MO25 complex2,3. This nucleotide-based mechanism established AMPK as the archetypal cellular fuel gauge.
However, nutrient availability and energy charge are not synonymous, and fluctuations in intracellular AMP, ADP, and ATP are often relatively limited. This suggests that adenine nucleotide levels alone may not fully account for AMPK regulation. Work from Zhang and colleagues showed that glucose deprivation can activate AMPK before substantial shifts in adenine nucleotide ratios occur. Under glucose-depleted conditions, loss of fructose-1,6-bisphosphate (FBP) from aldolase promotes assembly of a lysosomal AXIN–LKB1–AMPK complex, facilitating LKB1-dependent phosphorylation and activation of AMPK4-6, and providing the first example of AMPK regulation independent of detectable changes in energy charge.
Now, Wang et al. identify a more direct route linking glycolytic metabolism to AMPK7. Depletion of phosphoglycerate kinase 1 (PGK1) activated AMPK even under high-glucose conditions without appreciably altering the AMP/ATP or ADP/ATP ratios. Metabolomic analysis traced this response to three metabolites downstream of PGK1: 3-phosphoglycerate (3PG), 2-phosphoglycerate (2PG), and pyruvate. Notably, these metabolites continued to suppress AMPK in AXIN-null or TULP3-depleted cells, indicating a lysosome-independent mechanism.
Mechanistically, 3PG, 2PG, and pyruvate, glycolytic metabolites downstream of FBP, directly bind the LKB1 complex and inhibit LKB1-dependent AMPK phosphorylation. Structural and biochemical analyses further revealed a positively charged pocket within the LKB1 kinase domain that accommodates these metabolites. Such engagement remodels the activation loop and weakens ATP binding without disrupting the LKB1–STRAD–MO25 complex. In mouse liver, 3PG, 2PG, and pyruvate varied with feeding state and inversely tracked with AMPK activation. Heterozygous mice expressing metabolite-insensitive LKB1 maintained higher AMPK signaling and were resistant to high-fat-diet-induced adiposity, hepatic lipid accumulation, and glucose intolerance. Conversely, an activity-enhancing PGK1 allele increased downstream glycolytic metabolites and suppressed AMPK, whereas the PGK1 inhibitor MCB-330 lowered these metabolites, activated AMPK, and improved metabolic readouts in ob/ob mice. Together, these genetic and pharmacological data connect LKB1-mediated metabolite sensing to systemic metabolic homeostasis.
Viewed alongside the FBP-aldolase pathway, these findings reveal that AMPK is regulated by multiple glycolytic metabolites via distinct mechanisms. FBP controls the spatial assembly of the LKB1–AMPK machinery through aldolase, whereas 3PG, 2PG, and pyruvate directly tune LKB1 catalytic activity. Sampling glycolysis at distinct nodes may enable the AMPK pathway to distinguish nutrient availability from energetic stress and couple changes in metabolic state to an appropriate AMPK response. Intriguingly, AMPK regulation extends beyond glycolytic intermediates. Pentose phosphate pathway output has also been linked to LKB1–AMPK signaling8, while AMPKα2 can specifically respond to amino acid insufficiency through a GCN2-dependent mechanism9.
In the classical view, the mechanistic target of rapamycin (mTOR) and AMPK represent two major and opposing regulators of cellular metabolism. mTOR responds to nutrient-replete conditions to promote anabolism, whereas AMPK responds to energetic stress to promote catabolism and restrain biosynthesis. Emerging evidence that AMPK is regulated by diverse metabolites suggests that intermediary metabolite signaling is indispensable for cellular metabolic control. The notion that different metabolites convey regulatory signals to cellular metabolism is supported by the multisubunit architectures of mTOR and AMPK complexes, which are designed to respond to different metabolic stimuli, including metabolites, rather than respond solely to cellular energy charge. As metabolism provides not only energy for cellular activities but also metabolites as building blocks for biosynthesis, the regulation of AMPK by both energy status and metabolite availability positions AMPK as a metabolic pivot rather than merely a regulator of cellular energy charge (Fig. 1). This principle also applies to mTOR, whose activity is regulated by metabolites such as amino acids10. An unanswered question raised by these observations is why two distinct signaling complexes, mTOR and AMPK, are required to respond to metabolic status, given that both are sensitive to energy charge and metabolite availability. One possibility is that mTOR and AMPK integrate metabolite signals within distinct energetic contexts. That is, AMP binding may facilitate robust AMPK signaling under low-energy conditions, whereas ATP availability may modulate mTOR activity under energy-replete conditions. Future studies are warranted to test this hypothesis.

[1]

González, A., Hall, M.N., Lin, S.C. & Hardie, D.G. Cell Metab. 31, 472–492 (2020).

[2]

Hawley, S.A. et al. J. Biol. 2, 28 (2003).

[3]

Gowans, G.J., Hawley, S.A., Ross, F.A. & Hardie, D.G. Cell Metab. 18, 556–566 (2013).

[4]

Zhang, Y.L. et al. Cell Metab. 18, 546–555 (2013).

[5]

Zhang, C.S. et al. Cell Metab. 20, 526–540 (2014).

[6]

Zhang, C.S. et al. Nature 548, 112–116 (2017).

[7]

Wang, K.H. et al. Vita https://doi.org/10.15302/vita.2026.07.0056 (2026).

[8]

Lin, R.T. et al. Nat. Cell Biol. 17, 1484–1496 (2015).

[9]

Mao, Y.Z. et al. Cell Metab. 38, 192–207.e8 (2026).

[10]

Sancak, Y. et al. Science 320, 1496–1501 (2008).

RIGHTS & PERMISSIONS

The Author(s) 2026. Published by Higher Education Press. This is an Open Access article distributed under the terms of the CC BY license (https://creativecommons.org/licenses/by/4.0/).

Cite this article

Download citation ▾
Mao, Y., Zhao, S.  AMPK integrates energy and material metabolism  Vita https://doi.org/10.15302/vita.2026.08.0069 ()
AI Summary AI Mindmap
PDF (329KB)
Sections
Figures
References

0

Accesses

0

Citation

Detail

Recommended

AI思维导图

/

〈 〉