Let-7a induces metabolic reprogramming in breast cancer cells via targeting mitochondrial encoded ND4
Praveen Sharma1, Vibhuti Sharma2, Tarunveer Singh Ahluwalia3
1Molecular Medicine Laboratory, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India.
Background And Objectives:
MicroRNA (miRNA) that translocate from the nucleus to mitochondria are referred to as mitochondrial microRNA (mitomiR). Albeit mitomiRs have been shown to modulate gene expression, their functional impact within mitochondria is unknown. The main objective of this study is to investigate whether the mitochondrial genome is regulated by miR present inside the mitochondria.
Methods And Results:
Here, we report mitomiR let-7a regulates mitochondrial transcription in breast cancer cells and reprogram the metabolism accordingly. These effects were mediated through the interaction of let-7a with mtDNA, as studied by RNA pull-down assays, altering the activity of Complex I in a cell line-specific manner. Our study, for the first time, identifies the role of mitomiR (let-7a) in regulating the mitochondrial genome by transcriptional repression and its contribution to regulating mitochondrial metabolism of breast cancer cells.
Conclusion:
These findings uncover a novel mechanism by which mitomiR regulates mitochondrial transcription.
Insights
Mitochondrial microRNAs (mitomiRs) like let-7a regulate mitochondrial transcription and metabolism in breast cancer cells. This study reveals a novel mechanism of mitochondrial genome regulation by mitomiRs.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Mitochondrial microRNAs (mitomiRs) are nuclear-encoded miRNAs translocated into mitochondria.
- Their precise functional roles within mitochondria remain largely unexplored.
- Investigating mitomiR impact on mitochondrial gene expression is crucial.
Purpose of the Study:
- To determine if mitochondrial microRNAs regulate the mitochondrial genome.
- To elucidate the functional consequences of such regulation in cancer cells.
Main Methods:
- RNA pull-down assays to detect let-7a interaction with mitochondrial DNA (mtDNA).
- Analysis of mitochondrial transcription and Complex I activity.
- Cell line-specific metabolic profiling.
Main Results:
- Mitochondrial microRNA let-7a directly interacts with mtDNA.
- let-7a mediates transcriptional repression of the mitochondrial genome.
- This regulation alters mitochondrial metabolism and Complex I activity in breast cancer cells.
Conclusions:
- Identified a novel mechanism of mitochondrial genome regulation by mitomiR let-7a.
- Demonstrated mitomiR-mediated regulation of mitochondrial transcription and metabolism.
- Highlights a new regulatory pathway in breast cancer cell biology.
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