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Sphingolipid accumulation causes mitochondrial dysregulation and cell death
Jeffrey Knupp1, Fernando Martinez-Montañés2, Francoise Van Den Bergh3
1Department of Molecular Cellular and Developmental Biology, University of Michigan,Ann Arbor, MI, USA.
Cell Death and Differentiation
|August 12, 2017
Summary
Sphingolipid accumulation in yeast triggers Ras GTPase hyperactivation, mitochondrial dysfunction, and impacts cell survival. Restoring metabolic balance via Snf1/AMPK pathways or mitigating Ras activity rescues these cells.
Area of Science:
- Cell Biology
- Metabolic Biochemistry
- Yeast Genetics
Background:
- Sphingolipids are crucial cell membrane components with signaling functions.
- Dysregulated sphingolipid metabolism is linked to various diseases.
- Sphingolipid metabolism integrates with cellular signaling and energy homeostasis.
Purpose of the Study:
- To investigate the consequences of sphingolipid accumulation using a monogenic yeast model.
- To elucidate the role of inositol phosphorylceramide (IPC) in cellular signaling and mitochondrial function.
- To identify key pathways involved in sphingolipid-induced cellular stress.
Main Methods:
- Utilized a csg2Δ yeast mutant model for sphingolipid accumulation.
- Assessed Ras GTPase activation, mitochondrial reactive oxygen species (ROS) production, and mitochondrial mass.
- Investigated the role of Snf1/AMPK protein kinase in energy homeostasis.
- Evaluated rescue strategies including gene overexpression and pathway activation.
Main Results:
- The csg2Δ mutant accumulates inositol phosphorylceramide (IPC), leading to IPC-dependent Ras GTPase hyperactivation.
- Accumulated IPC caused increased mitochondrial ROS and reduced mitochondrial mass.
- Cell survival was dependent on nutritional status, linked to impaired Snf1/AMPK activity.
- Overexpression of mitochondrial catalase (Cta1), Ras abrogation, or Snf1/AMPK activation rescued csg2Δ cells.
Conclusions:
- Sphingolipid dysregulation, specifically IPC accumulation, compromises metabolic integrity.
- The Ras and Snf1/AMPK pathways are critical mediators of sphingolipid-induced cellular stress.
- Yeast models provide insights into fundamental mechanisms of sphingolipid metabolism and disease.
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