image: mTORC1 activation requires the coordinated input of amino acid sufficiency and growth factor signaling, operating as an “AND” gate. To ensure both conditions are met, mTORC1 must first translocate to the lysosomal surface by anchoring onto the Rag GTPases, a step gated by amino acid availability. Cytosolic amino acids are detected by direct sensors, including CASTOR1 (arginine), Sestrin2, SAR1B, and LARS (leucine), that converge on the GATOR1-GATOR2 axis, which modulates the Rag-Ragulator complex. In addition, amino acid availability can be sensed by the FLCN/FNIP complex, which regulates Rag complex configuration since it is a GAP for Rag C/D. Metabolic derivatives of amino acids can also regulate mTORC1 via distinct, Rag-dependent or Rag-independent mechanisms. Lysosomal amino acids are communicated via the lysosomal transmembrane protein SLC38A9 to the Ragulator-Rag machinery. Once recruited to the lysosome, mTORC1 can be activated by GTP-bound Rheb, whose loading state is governed by the TSC complex, the principal brake on mTORC1 that integrates growth factor signaling and stress-responsive inputs including energy status (AMPK), DNA damage (p53), and hypoxia (REDD1). Thus, full kinase activation occurs only when both arms are simultaneously engaged. Positive regulators are indicated in red and negative regulators in blue. mTORC1: mechanistic target of rapamycin complex 1; SAM: S-adenosylmethionine; SAMTOR: SAM sensor upstream of mTORC1; CASTOR1: cellular arginine sensor for mTORC1 subunit 1; SAR1B: secretion-associated Ras-related GTPase 1B; LARS: leucyl-tRNA synthetase 1, cytosolic; GATOR1/2: GAP activity toward Rags complex 1/2; KICSTOR: KPTN–ITFG2–C12orf66–SZT2 complex; FLCN: folliculin; α-KG: α-ketoglutarate; v-ATPase: vacuolar-type H+-ATPase; Rag: Ras-related GTP-binding protein; Ragulator: Ragulator complex (or late endosomal/lysosomal adaptor and MAPK and mTOR activator, LAMTOR); SLC38A9: solute carrier family 38 member 9; Rheb: Ras homolog enriched in brain; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; TSC: tuberous sclerosis complex; AMPK: AMP-activated protein kinase; p53: tumor protein p53; REDD1: regulated in development and DNA damage responses 1.
Credit: © David C. Rubinsztein*, et al. 2026. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Researchers from the University of Cambridge highlight new ways that neurons and many cell types use to sense nutrients — opening potential novel therapeutic avenues for disorders such as Alzheimer's and Parkinson's disease.
Neurons are among the longest-living cells in the human body. Unlike many other cell types, they cannot dilute damaged proteins through cell division and therefore rely heavily on tightly controlled systems that regulate nutrient sensing, protein quality control, and autophagy — the cellular "self-cleaning" process essential for neuronal survival.
In a new review published in EXO – Beyond the Cell, researchers led by Prof. David C. Rubinsztein from the University of Cambridge discuss emerging evidence that neurons may use a previously underappreciated metabolic mechanism to regulate mTORC1, a central signaling hub that coordinates cellular growth, metabolism, and autophagy.
For years, canonical amino acid sensing pathways — such as Sestrin2-mediated leucine sensing — have dominated the field of mTORC1 biology. These studies have been largely conducted in HEK293 cells. However, the researchers highlight growing evidence that in neurons and glial cells, as well as numerous other cell types, leucine-derived acetyl-coenzyme A (AcCoA) may play a more prominent regulatory role. In this pathway, AcCoA activates the acetyltransferase p300, leading to acetylation of the mTORC1 component Raptor and subsequent activation of mTORC1 signaling.
Importantly, chronic overactivation of mTORC1 has been linked to impaired autophagy and toxic protein accumulation across multiple neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and ALS.
Rather than directly suppressing mTORC1, the researchers suggest that targeting upstream metabolic nodes could represent an alternative therapeutic strategy.
In this review, researchers also summarize evidence that metabolic and inflammatory pathways may converge on neuronal mTORC1 regulation. For example, abnormal AcCoA accumulation and inflammatory signaling through CCR5 represent two different mechanisms that have been implicated in pathological mTORC1 activation and autophagy defects in neurodegenerative disease models.
"These findings suggest that neuronal nutrient sensing may have differences to what is seen in HEK293 cells, which have been used extensively in the previous literature," the researchers note. "Understanding these specialized metabolic control mechanisms could help identify new therapeutic opportunities upstream of mTORC1."
The researchers further highlight several emerging therapeutic directions, including modulation of AcCoA production, regulation of p300 acetylation activity, and targeting inflammatory-metabolic crosstalk pathways.
The review, "Nutrient-sensing and mTORC1 regulation in neuronal homeostasis: from metabolic signaling to neurodegeneration," was published in EXO – Beyond the Cell.
Method of Research
Literature review
Subject of Research
Not applicable
Article Title
Nutrient-sensing and mTORC1 regulation in neuronal homeostasis: from metabolic signaling to neurodegeneration
Article Publication Date
15-May-2026
COI Statement
D.C.R has consulted for or is a consultant for Drishti Discoveries, PAQ Therapeutics, MindRank AI, Retro Biosciences, Alexion Pharma International Operations Limited, Carlyle Investment Management LLC, Aladdin Healthcare Technologies Ltd, Nido Biosciences, ProtosBio, and is a co-founder of Acuity Technologies Ltd. All other authors declare no conflicts of interest.