Myostatin induces mitochondrial metabolic alteration and typical apoptosis in cancer cells
1The State Key Laboratory of Biomembrane and Membrane Biotechnology, Chinese Academy of Sciences, Beijing, China.
Abstract:
Myostatin, a member of the transforming growth factor-β superfamily, regulates the glucose metabolism of muscle cells, while dysregulated myostatin activity is associated with a number of metabolic disorders, including muscle cachexia, obesity and type II diabetes. We observed that myostatin induced significant mitochondrial metabolic alterations and prolonged exposure of myostatin induced mitochondria-dependent apoptosis in cancer cells addicted to glycolysis. To address the underlying mechanism, we found that the protein levels of Hexokinase II (HKII) and voltage-dependent anion channel 1 (VDAC1), two key regulators of glucose metabolisms as well as metabolic stress-induced apoptosis, were negatively correlated. In particular, VDAC1 was dramatically upregulated in cells that are sensitive to myostatin treatment whereas HKII was downregulated and dissociated from mitochondria. Myostatin promoted the translocation of Bax from cytosol to mitochondria, and knockdown of VDAC1 inhibited myostatin-induced Bax translocation and apoptosis. These apoptotic changes can be partially rescued by repletion of ATP, or by ectopic expression of HKII, suggesting that perturbation of mitochondrial metabolism is causally linked with subsequent apoptosis. Our findings reveal novel function of myostatin in regulating mitochondrial metabolism and apoptosis in cancer cells.
Insights
Myostatin disrupts mitochondrial metabolism and induces apoptosis in cancer cells by altering glucose metabolism regulators Hexokinase II and VDAC1. This reveals a novel role for myostatin in cancer cell death.
Area of Science:
- Cell Biology
- Metabolic Regulation
- Cancer Research
Background:
- Myostatin, a TGF-β superfamily member, influences muscle glucose metabolism.
- Dysregulated myostatin is linked to metabolic disorders like obesity and type II diabetes.
- Cancer cells often rely on glycolysis, making them potentially vulnerable to metabolic interventions.
Purpose of the Study:
- To investigate myostatin's role in mitochondrial metabolism and apoptosis in cancer cells.
- To elucidate the molecular mechanisms underlying myostatin-induced apoptosis.
- To identify key regulators involved in myostatin's effects on glucose metabolism and cell death.
Main Methods:
- Analysis of mitochondrial metabolic alterations induced by myostatin.
- Assessment of protein levels and localization of Hexokinase II (HKII) and VDAC1.
- Investigation of Bax translocation and apoptosis using knockdown and rescue experiments.
- Measurement of ATP levels and HKII expression for functional rescue.
Main Results:
- Myostatin induced significant mitochondrial metabolic changes and apoptosis in glycolysis-addicted cancer cells.
- A negative correlation was observed between HKII and VDAC1 protein levels.
- VDAC1 upregulation and HKII downregulation/mitochondrial dissociation were noted in myostatin-sensitive cells.
- Myostatin promoted Bax translocation to mitochondria, which was inhibited by VDAC1 knockdown.
- Apoptosis could be partially rescued by ATP repletion or HKII re-expression.
Conclusions:
- Myostatin plays a novel role in regulating mitochondrial metabolism and apoptosis in cancer cells.
- Perturbation of mitochondrial metabolism by myostatin is causally linked to cancer cell apoptosis.
- VDAC1 and HKII are critical mediators of myostatin-induced apoptosis, highlighting potential therapeutic targets.
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