ER-mitochondria signaling regulates autophagy

Abstract

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.

Keywords: PTPIP51; VAPB; autophagy; calcium; endoplasmic reticulum; mitochondria; mitochondria-associated membranes.

Figure 1.

Diagram ilustrating the proposed mechanism by which the VAPB-RMDN3 ER-mitochondria tethering complex regulates autophagy. (A) VAPB or RMDN3 overexpression tightens ER-mitochondria contacts to enhance ITPR-mediated Ca²⁺ delivery to mitochondria, which in turn inhibits autophagosome formation. (B) siRNA-dependent loss of VAPB or RMDN3 loosens ER-mitochondria contacts to inhibit Ca²⁺ delivery and stimulate autophagosome formation.