Abstract
SummaryFructose-1,6-bisphosphate (FBP) aldolase links sensing of declining glucose availability to AMPK activation via the lysosomal pathway. However, how aldolase transmits lack of occupancy by FBP to AMPK activation remains unclear. Here, we show that FBP-unoccupied aldolase interacts with and inhibits endoplasmic reticulum (ER)-localized transient receptor potential channel subfamily V, inhibiting calcium release in low glucose. The decrease of calcium at contact sites between ER and lysosome renders the inhibited TRPV accessible to bind the lysosomal v-ATPase that then recruits AXIN:LKB1 to activate AMPK independently of AMP. Genetic depletion of TRPVs blocks glucose starvation-induced AMPK activation in cells and liver of mice, and in nematodes, indicative of physical requirement of TRPVs. Pharmacological inhibition of TRPVs activates AMPK and elevates NAD+ levels in aged muscles, rejuvenating the animals’ running capacity. Our study elucidates that TRPVs relay the FBP-free status of aldolase to the reconfiguration of v-ATPase, leading to AMPK activation in low glucose.
Highlights
AMP-activated protein kinase (AMPK) is a pivotal sensor for monitoring cellular energy state and nutrient supply (Carling et al, 2012; Herzig and Shaw, 2018; Lin and Hardie, 2018; Steinberg and Kemp, 2009)
TRPV1–4 Interact with FBP-Unoccupied Aldolase and Are Required for Lysosomal AMPK Activation in Low Glucose To search for factors that might transmit sensing of the absence of FBP by aldolase to the conformational changes of v-ATPase, we performed mass spectrometry of protein complexes coimmunoprecipitated with ALDOA from light organelle fractions containing lysosomes
We were intrigued by one candidate, TRPV4, which belongs to the V subfamily of transient receptor potential (TRP) channels, which play a variety of roles in different tissues in response to chemical and physical stimuli (Clapham, 2003; Nilius and Flockerzi, 2014)
Summary
AMP-activated protein kinase (AMPK) is a pivotal sensor for monitoring cellular energy state and nutrient supply (Carling et al, 2012; Herzig and Shaw, 2018; Lin and Hardie, 2018; Steinberg and Kemp, 2009). It occurs universally as heterotrimeric complexes containing catalytic a subunits and regulatory b, and g subunits, with the g subunit providing the binding sites for the regulatory adenine nucleotides, AMP, ADP, and ATP. Given that aging and decreased muscular fitness is associated with decreased AMPK, the investigators were able to pharmacologically increase AMPK levels in aged muscles, something that has previously proved quite challenging, and show that the treated aged mice doubled their running capacity
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