Glucose restriction drives spatial reorganization of mevalonate metabolism
- University of Texas Southwestern Medical Center, United States
Abstract
Eukaryotes compartmentalize metabolic pathways into sub-cellular domains, but the role of inter-organelle contacts in organizing metabolic reactions remains poorly understood. Here, we show that in response to acute glucose restriction (AGR) yeast undergo metabolic remodeling of their mevalonate pathway that is spatially coordinated at nucleus-vacuole junctions (NVJs). The NVJ serves as a metabolic platform by selectively retaining HMG-CoA Reductases (HMGCRs), driving mevalonate pathway flux in an Upc2-dependent manner. Both spatial retention of HMGCRs and increased mevalonate pathway flux during AGR is dependent on NVJ tether Nvj1. Furthermore, we demonstrate that HMGCRs associate into high molecular weight assemblies during AGR in an Nvj1-dependent manner. Loss of Nvj1-mediated HMGCR partitioning can be bypassed by artificially multimerizing HMGCRs, indicating NVJ compartmentalization enhances mevalonate pathway flux by promoting the association of HMGCRs in high molecular weight assemblies. Loss of HMGCR compartmentalization perturbs yeast growth following glucose starvation, indicating it promotes adaptive metabolic remodeling. Collectively we propose a non-canonical mechanism regulating mevalonate metabolism via the spatial compartmentalization of rate-limiting HMGCR enzymes at an inter-organelle contact site.
Data availability
All data in the BioRvix paper:https://www.biorxiv.org/content/10.1101/2020.08.29.273318v1.full
Article and author information
Author details
Natalie Ortiz Speer
Funding
Welch Foundation (I-1873)
- W Mike Henne
National Institute of General Medical Sciences (GM119768)
- W Mike Henne
National Institute of General Medical Sciences (5T32GM008297)
- Sean M Rogers
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Rogers et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Glucose restriction drives spatial reorganization of mevalonate metabolism
eLife 10:e62591.
https://doi.org/10.7554/eLife.62591
