Glucose restriction drives spatial reorganization of mevalonate metabolism.

Sean Rogers,N Ezgi Wood,Hanaa Hariri,W Mike Henne,Natalie Ortiz Speer

doi:10.7554/elife.62591

Sean Rogers, N Ezgi Wood + Show 3 more

Open Access

https://doi.org/10.7554/elife.62591

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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.

Highlights

The complexity of eukaryotic metabolism requires spatial organization, so membranebound and membraneless organelles compartmentalize enzymes into distinct sub-cellular regions
Given that endoplasmic reticulum (ER)-mediated contact sites in Saccharomyces cerevisiae act as lipogenic domains, we visually screened GFP-tagged neutral lipid metabolism enzymes for signs of compartmentalization at ER inter-organelle contact sites in yeast exposed to acute glucose restriction (AGR)
Reductases (HMGCR) Hmg1 and Hmg2, which localize throughout ER network and on the nuclear envelope (NE), enriched at the regions where the nuclear surface was in contact with the vacuole following AGR (Figure 1A)

Summary

18 Abstract

19 Eukaryotes compartmentalize metabolic pathways into sub-cellular domains, but the role of inter-organelle contacts in organizing metabolic reactions remains poorly understood. 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 Nvj. We demonstrate that HMGCRs associate into high molecular weight assemblies during AGR in an Nvj1-dependent manner. 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. We propose a non-canonical mechanism regulating mevalonate metabolism via the spatial compartmentalization of rate-limiting HMGCR enzymes at an inter-organelle contact site

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Materials and Methods