# Spatial determinants in lipid metabolic organization at the sub-organelle level

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $410,000

## Abstract

Project Summary/Abstract
To adapt to metabolic cues and survive stresses like nutrient starvation, cells store high-
energy lipids in specialized organelles called lipid droplets (LDs) that emerge from the
endoplasmic reticulum (ER), the metabolic center of cells. Recent studies reveal that
LDs serve many roles in cell physiology, but how they are functionally ear-marked for
specific tasks is unclear. Indeed, the ER network itself executes numerous cellular
functions, but how this functional diversity is mechanistically achieved is unclear. The
purpose of this grant is to dissect the molecular mechanisms by which LDs and
the ER network achieve functional diversity at the sub-organelle level. Capitalizing
on published and preliminary data, we find that LDs exhibit unique surface proteomes
that provide functional specificity for LDs within single cells. Furthermore, we find that
inter-organelle contact sites define ER sub-domains with specific roles in the
compartmentalization of mevalonate metabolism. Here, I outline three directions that
enable the mechanistic dissection of LD and ER functional compartmentalization:
1) In direction 1, we will leverage yeast genetics, biochemistry, and metabolic
 dissection to dissect how yeast ER-lysosome contacts (called nucleus-vacuole
 junctions, NVJs) serve as ER sub-domains and “metabolic platforms” that spatially
 compartmentalize mevalonate metabolism, and promote metabolic remodeling
 during glucose starvation.
2) In direction 2, we will capitalize on a large-scale screen to dissect how LDs are
 labeled with specific proteins to enable unique roles within cells.
3) In direction 3, we will utilize state-of-the-art cryo-FIB-SEM imaging to dissect how
 lipid phase transitions within LDs selectively remodel the LD surface proteome, and
 ultimately influence LD function and LD inter-organelle contact sites.
Collectively, these directions will provide insights into new cellular organizational
principles that enable to LDs and the ER network to achieve a functional division-of-
labor. They will also characterize lipid phase transition properties of sterols, which
promote disease pathologies in obesity, heart disease, and atherosclerosis.

## Key facts

- **NIH application ID:** 10330494
- **Project number:** 2R35GM119768-06
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Mike Henne
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $410,000
- **Award type:** 2
- **Project period:** 2016-08-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10330494

## Citation

> US National Institutes of Health, RePORTER application 10330494, Spatial determinants in lipid metabolic organization at the sub-organelle level (2R35GM119768-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10330494. Licensed CC0.

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