The ER-Mitochondria Tethering Complex VAPB-PTPIP51 Regulates Autophagy
Patricia Gomez-Suaga1, Sebastien Paillusson1, Radu Stoica1
1Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9RX, UK.
Current Biology : CB
|January 31, 2017
Summary
The VAPB-PTPIP51 tethers link the endoplasmic reticulum (ER) and mitochondria, regulating autophagy. Tightening these contacts impairs autophagy, while loosening them stimulates it, revealing a new mechanism for cellular control.
Area of Science:
- Cell Biology
- Mitochondrial Function
- Autophagy Regulation
Background:
- Mitochondria and endoplasmic reticulum (ER) form physical associations crucial for cellular functions.
- The VAPB-PTPIP51 complex acts as a scaffold, tethering ER to mitochondria.
Purpose of the Study:
- To investigate the role of VAPB-PTPIP51 tethers in regulating autophagy.
- To elucidate the mechanism by which ER-mitochondria contacts influence autophagosome formation.
Main Methods:
- Overexpression and siRNA-mediated knockdown of VAPB and PTPIP51.
- Utilizing a synthetic linker protein to artificially tether ER and mitochondria.
- Monitoring autophagosome formation and calcium (Ca2+) delivery.
Main Results:
- Overexpression of VAPB/PTPIP51 (tightening contacts) impairs autophagy; siRNA knockdown (loosening contacts) stimulates it.
- Artificial tethering mimics the effects of VAPB/PTPIP51 manipulation on autophagy.
- ER-mitochondria tethering affects specific autophagy induction pathways (rapamycin/torin 1) but not starvation-induced autophagy.
- VAPB-PTPIP51 tethers mediate Ca2+ transfer from ER to mitochondria, impacting autophagy.
Conclusions:
- The VAPB-PTPIP51 ER-mitochondria tethers are key regulators of autophagy.
- Autophagy regulation by ER-mitochondria contacts is stimulus-dependent.
- Calcium signaling between ER and mitochondria, mediated by VAPB-PTPIP51, is a novel mechanism controlling autophagy.
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