ER-mitochondria signaling regulates autophagy

TY - JOUR

T1 - ER-mitochondria signaling regulates autophagy

AU - Gomez-Suaga, Patricia

AU - Paillusson, Sebastien

AU - Miller, Christopher C.J.

PY - 2017/5/26

Y1 - 2017/5/26

N2 - The endoplasmic reticulum (ER) and mitochondria form tight functional contacts that regulate several key cellular processes. The formation of these contacts involves “tethering proteins” that function to recruit regions of ER to mitochondria. The integral ER protein VAPB (VAMP associated protein B and C) binds to the outer mitochondrial membrane protein, RMDN3/PTPIP51 (regulator of microtubule dynamics 3) to form one such set of tethers. Recently, we showed that the VAPB-RMDN3 tethers regulate macroautophagy/autophagy. Small interfering RNA (siRNA) knockdown of VAPB or RMDN3 to loosen ER-mitochondria contacts stimulates autophagosome formation, whereas overexpression of VAPB or RMDN3 to tighten contacts inhibit their formation. Artificial tethering of ER and mitochondria via expression of a synthetic linker protein also reduces autophagy and this artificial tether rescues the effects of VAPB- or RMDN3-targeted siRNA loss on autophagosome formation. Finally, our studies revealed that the modulatory effects of ER-mitochondria contacts on autophagy involve their role in mediating ITPR (inositol 1,4,5-trisphosphate receptor) delivery of Ca2+ from ER stores to mitochondria.

AB - The endoplasmic reticulum (ER) and mitochondria form tight functional contacts that regulate several key cellular processes. The formation of these contacts involves “tethering proteins” that function to recruit regions of ER to mitochondria. The integral ER protein VAPB (VAMP associated protein B and C) binds to the outer mitochondrial membrane protein, RMDN3/PTPIP51 (regulator of microtubule dynamics 3) to form one such set of tethers. Recently, we showed that the VAPB-RMDN3 tethers regulate macroautophagy/autophagy. Small interfering RNA (siRNA) knockdown of VAPB or RMDN3 to loosen ER-mitochondria contacts stimulates autophagosome formation, whereas overexpression of VAPB or RMDN3 to tighten contacts inhibit their formation. Artificial tethering of ER and mitochondria via expression of a synthetic linker protein also reduces autophagy and this artificial tether rescues the effects of VAPB- or RMDN3-targeted siRNA loss on autophagosome formation. Finally, our studies revealed that the modulatory effects of ER-mitochondria contacts on autophagy involve their role in mediating ITPR (inositol 1,4,5-trisphosphate receptor) delivery of Ca2+ from ER stores to mitochondria.

KW - autophagy

KW - calcium

KW - endoplasmic reticulum

KW - mitochondria

KW - mitochondria-associated membranes

KW - PTPIP51

KW - VAPB

UR - http://www.scopus.com/inward/record.url?scp=85020675429&partnerID=8YFLogxK

U2 - 10.1080/15548627.2017.1317913

DO - 10.1080/15548627.2017.1317913

M3 - Article

AN - SCOPUS:85020675429

SN - 1554-8627

SP - 1

EP - 2

JO - Autophagy

JF - Autophagy

ER -