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A chemical screen probing the relationship between mitochondrial content and cell size
Toshimori Kitami1, David J Logan, Joseph Negri
1Broad Institute, Cambridge, Massachusetts, United States of America.
Plos One
|April 6, 2012
Summary
Researchers screened thousands of molecules to find those affecting mitochondrial content. One compound, BRD6897, uniquely increases mitochondrial function without altering cell size, suggesting a novel mechanism for mitochondrial regulation.
Area of Science:
- Cell Biology
- Biochemistry
- Drug Discovery
Background:
- Mitochondrial content dynamically changes but underlying mechanisms are unclear.
- Identifying regulators of mitochondrial abundance is crucial for understanding cellular processes.
Purpose of the Study:
- To systematically identify molecular probes and pathways controlling mitochondrial abundance.
- To find compounds that modulate mitochondrial content independently of cell size.
Main Methods:
- Developed a high-throughput imaging assay to measure per-cell mitochondrial content and cell size.
- Screened 28,786 small molecules using human umbilical vein endothelial cells.
- Conducted secondary assays including fluorescence microscopy, protein content analysis, respiration measurements, and electron microscopy for compound BRD6897.
Main Results:
- Hundreds of small molecules altered mitochondrial content proportionally to cell size.
- A few compounds, including BRD6897, dissociated this relationship.
- BRD6897 significantly increased mitochondrial content and uncoupled respiration (1.6-fold) in non-dividing cells, independent of cell size or volume.
- BRD6897 increased mitochondrial electron density, not the proportion of mitochondria in the cytoplasm.
- The mechanism appears independent of transcriptional programs and may involve blocked mitochondrial protein turnover.
Conclusions:
- BRD6897 represents a novel tool for studying mitochondrial regulation.
- The compound's mechanism, potentially related to protein turnover, offers new insights into mitochondrial biogenesis and maintenance.
- Elucidating BRD6897's molecular target could reveal critical pathways governing mitochondrial homeostasis.
