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Fluorescence-Based Measurements of Phosphatidylserine/Phosphatidylinositol 4-Phosphate Exchange Between Membranes
Published on: March 14, 2021
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Peroxisomal-derived ether phospholipids link nucleotides to respirasome assembly
Christopher F Bennett1,2, Katherine E O'Malley1,2, Elizabeth A Perry1,2
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Nature Chemical Biology
|March 16, 2021
Summary
Inhibiting dihydroorotate dehydrogenase (DHODH) boosts mitochondrial respirasome assembly. This process involves nucleotide pools signaling to peroxisomes, affecting ether phospholipids essential for cell growth.
Area of Science:
- Mitochondrial biology
- Cellular metabolism
- Biochemistry
Background:
- Mitochondrial electron transport chain (ETC) complexes assemble into supercomplexes (SCs) or respirasomes.
- Mechanisms regulating respirasome assembly, specifically SC I+III2+IV, remain largely unknown.
- Understanding SC regulation is crucial for cellular energy production and function.
Purpose of the Study:
- To investigate the regulation of respirasome assembly.
- To identify factors influencing SC formation in vivo.
- To elucidate the link between nucleotide synthesis and mitochondrial function.
Main Methods:
- Development of a nanoluciferase complementation reporter for assessing complex III and IV proximity.
- Chemical screening to identify modulators of respirasome assembly.
- Uridine supplementation to bypass dihydroorotate dehydrogenase (DHODH) inhibition.
- Analysis of mitochondrial phospholipid composition, focusing on ether phospholipids.
Main Results:
- Inhibitors of DHODH significantly enhance respirasome assembly and activity.
- DHODH inhibition leads to increased SC formation and mitochondrial activity.
- Uridine supplementation reverses SC assembly by altering mitochondrial ether phospholipid levels.
- Cell growth under DHODH inhibition is dependent on ether lipid synthesis and SC assembly.
Conclusions:
- Nucleotide pools act as signals to peroxisomes, modulating ether phospholipid synthesis and transport.
- Ether phospholipids are critical for mitochondrial supercomplex assembly.
- Supercomplex assembly is essential for optimal cell growth under conditions of nucleotide limitation.
- DHODH inhibition represents a potential therapeutic target for modulating mitochondrial function.
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