期刊
CELL BIOLOGY AND TOXICOLOGY
卷 38, 期 3, 页码 469-485出版社
SPRINGER
DOI: 10.1007/s10565-021-09623-y
关键词
Cd; Autophagy; Calcium; MAMs; PC12 cells; Primary neurons
资金
- National Natural Science Foundation of China [31802260, 31772808, 31872533, 31702305]
- Natural Science Research of Higher Education in Jiangsu Province [18KJB230009]
- Jiangsu Provincial Natural Science Foundation of China [BK20180917]
- National Key Research and Development Program of China [2016YFD0501208]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
This study reveals that cadmium-induced neurotoxicity alters MAMs and mitochondrial Ca2+ levels, with Mfn2 playing a crucial role. Defects in Mfn2 affect mitochondrial Ca2+ uptake efficiency and autophagy. The mechanism involving IP3R-Grp75-VDAC1 tethers in MAMs is associated with the regulation of autophagy by Mfn2 and their role in mediating mitochondrial Ca2+ uptake from ER stores.
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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