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Updated: May 23, 2025
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Author Spotlight: Advancing Techniques and Discoveries in Protein Synthesis and Assembly Through Innovative Mitochondrial Research
Published on: June 7, 2024
841
Oxidation of retromer complex controls mitochondrial translation
Junbing Zhang1,2, Md Yousuf Ali3, Harrison Byron Chong3
1Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA, USA. junbingzhang@sinh.ac.cn.
Nature
|March 27, 2025
Summary
Scientists discovered that VPS35 protein senses reactive oxygen species (ROS) and regulates mitochondrial translation. This finding connects cellular ROS levels to mitochondrial ROS production and impacts cancer therapy.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Reactive oxygen species (ROS) are implicated in human diseases like cancer and neurodegeneration.
- Proteins that sense ROS via cysteine residues and regulate ROS production are not well understood.
Purpose of the Study:
- To identify proteins and mechanisms that sense cellular reactive oxygen species (ROS) and regulate mitochondrial ROS production.
- To elucidate the role of VPS35 in a ROS-sensing pathway.
Main Methods:
- Systematic base-editing and computational screens were employed.
- Cysteine residues in VPS35 were investigated for their role in ROS sensing.
- Retromer complex function and plasma membrane localization of SLC7A1 were analyzed.
Main Results:
- VPS35 cysteines were identified as ROS sensors, regulating mitochondrial translation.
- Oxidation of VPS35 cysteines by hydrogen peroxide leads to retromer dissociation and plasma membrane remodeling.
- Plasma membrane localization of SLC7A1 is crucial for maintaining mitochondrial translation.
- Reduced VPS35 or oxidized cysteines confer resistance to ROS-generating chemotherapy in ovarian cancer models.
Conclusions:
- VPS35 acts as a sensor for intracellular ROS, linking cytosolic ROS levels to mitochondrial ROS production via regulation of mitochondrial translation.
- This pathway involves VPS35-mediated retromer dynamics and SLC7A1 plasma membrane localization.
- Targeting this VPS35-mediated pathway may offer new strategies for cancer therapy.
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