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Ca2+ transfer via the ER-mitochondria tethering complex in neuronal cells contribute to cadmium-induced autophagy

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Abstract

Mitochondrial-associated endoplasmic reticulum (ER) membranes (MAMs) play a key role in several physiological functions, including calcium ion (Ca2+) 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 Ca2+ 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 Ca2+ 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 Ca2+ uniporter inhibitor RuR blocked both mitochondrial Ca2+ 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 Ca2+ uptake from ER stores. These results give new evidence into the organelle metabolic process by demonstrating that Ca2+ transport between ER-mitochondria is important in autophagosome formation in Cd-induced neurodegeneration.

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All relevant data and materials are available from the authors upon reasonable request.

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Acknowledgements

We thank Dr. Liqi Zhu for giving us the plasmid as gift, Dr. Mahmoud for providing language help, and the Testing Center of Yangzhou University for providing technical support for the use of laser confocal microscopy. We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

Funding

This study was supported by grants from the National Natural Science Foundation of China (Nos. 31802260, 31772808, 31872533, and 31702305), Natural Science Research of Higher Education in Jiangsu Province (18KJB230009), Jiangsu Provincial Natural Science Foundation of China (BK20180917), and the National Key Research and Development Program of China (No. 2016YFD0501208), a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Contributions

TW and YY conceived and designed the study. TW, QPZ, and BBC performed the experiments. SQW, JCB, HZ, XZL, and JHG contributed materials and methods. YC and RLS analyzed the data. TW wrote the manuscript. ZPL performed the final approval of the version to be submitted.

Corresponding authors

Correspondence to Zongping Liu or Yan Yuan.

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The ethics committee of Yangzhou University (Yangzhou, China) approved all animal experiments.

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The authors declare no competing interests.

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Highlights

• Cd triggers alterations of MAMs and mitochondrial Ca2+ levels in neuronal cells.

• Ablation or silencing of Mfn2 blocks the colocalization of ER and mitochondria.

• Mfn2 defect reduces Grp75-VDAC1 interaction and mitochondrial Ca2+ uptake.

• Mutation of Mfn2 or Grp75 suppressed Cd-induced autophagy.

• Autophagy induced by Cd is blocked by the inhibition of mitochondrial Ca2+ uptake.

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Wang, T., Zhu, Q., Cao, B. et al. Ca2+ transfer via the ER-mitochondria tethering complex in neuronal cells contribute to cadmium-induced autophagy. Cell Biol Toxicol 38, 469–485 (2022). https://doi.org/10.1007/s10565-021-09623-y

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  • DOI: https://doi.org/10.1007/s10565-021-09623-y

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