# Sphingolipid signaling in mitochondrial surveillance

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $360,938

## Abstract

Project Summary
Sphingolipids regulate a multitude of cellular and physiological processes and dysregulation of sphingolipid
signaling is associated with cardiovascular and neurodegenerative disorders, and stroke. The long-term
goal of the proposed research is to identify the cellular and molecular mechanisms by which sphingosine-
1-phospate (S1P), generated by sphingosine kinase, regulates the activation of the mitochondrial unfolded
protein response (UPRmt). The UPRmt is critical for maintaining mitochondrial protein homeostasis in
response to mitochondrial stress, but molecular mechanisms underlying its activation are not fully
understood. My laboratory uses the model C. elegans to study the role of sphingolipid signaling in
regulating neuronal function and neurotransmitter release. We recently uncovered a novel function for the
sole sphingosine kinase ortholog, SPHK-1, in activating the UPRmt and in promoting organism-wide
protection in response to a broad array of mitochondrial stressors. We found that SPHK-1 associates with
mitochondria and that this association is regulated by mitochondrial stress generated either cell
autonomously (in the intestine) or cell non-autonomously (by the nervous system). Here we seek to
uncover the cellular and molecular mechanisms by which sphingolipid signaling is regulated during the
UPRmt, how it activates the UPRmt and how it impacts mitochondrial homeostasis and survival in
multicellular organisms. In Aim 1, we determine the molecular mechanism by which mitochondrial stress
regulates SPHK-1 targeting and function. In Aim 2, we determine how neuroendocrine signaling regulates
sphingolipid signaling during the UPRmt. In Aim 3, we identify cellular targets of S1P during the UPRmt and
how they regulate transcriptional responses to ensure proper cellular homeostasis and survival in the face
of stress. This proposal will advance mechanistic understanding of how mitochondrial sphingosine kinase
is regulated and signals in vivo, and will further understanding of the mechanism underlying activation of
the UPRmt.

## Key facts

- **NIH application ID:** 10683149
- **Project number:** 5R01NS110730-05
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** DEREK SIEBURTH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $360,938
- **Award type:** 5
- **Project period:** 2019-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10683149

## Citation

> US National Institutes of Health, RePORTER application 10683149, Sphingolipid signaling in mitochondrial surveillance (5R01NS110730-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10683149. Licensed CC0.

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