Ca transfer via the ER-mitochondria tethering complex in neuronal cells contribute to cadmium-induced autophagy.

Mitochondrial-associated endoplasmic reticulum (ER) membranes (MAMs) play a key role in several physiological functions, including calcium ion (Ca) transfer and autophagy; however, the molecular mechanism controlling this interaction in cadmium (Cd)-induced neurotoxicity is unknown. This study shows that Cd induces alterations in MAMs and mitochondrial Ca levels in PC12 cells and primary neurons. Ablation or silencing of mitofusin 2 (Mfn2) in PC12 cells or primary neurons blocks the colocalization of ER and mitochondria while reducing the efficiency of mitochondrial Ca uptake. Moreover, Mfn2 defects reduce interactions or colocalization between GRP75 and VDAC1. Interestingly, the enhancement of autophagic protein levels, colocalization of LC3 and Lamp2, and GFP-LC3 puncta induced by Cd decreased in Mfn2 or Grp75 PC12 cells and Mfn2- or Grp75-silenced primary neurons. Notably, the specific Ca uniporter inhibitor RuR blocked both mitochondrial Ca uptake and autophagy induced by Cd. Finally, this study proves that the mechanism by which IP3R-Grp75-VDAC1 tethers in MAMs is associated with the regulation of autophagy by Mfn2 and involves their role in mediating mitochondrial Ca uptake from ER stores. These results give new evidence into the organelle metabolic process by demonstrating that Ca transport between ER-mitochondria is important in autophagosome formation in Cd-induced neurodegeneration.