Bibliographic Details
| Title: |
Mitochondrial Calcium-Triggered Oxidative Stress and Developmental Defects in Dopaminergic Neurons Differentiated from Deciduous Teeth-Derived Dental Pulp Stem Cells with MFF Insufficiency |
| Authors: |
Xiao Sun, Shuangshan Dong, Hiroki Kato, Jun Kong, Yosuke Ito, Yuta Hirofuji, Hiroshi Sato, Takahiro A. Kato, Yasunari Sakai, Shouichi Ohga, Satoshi Fukumoto, Keiji Masuda |
| Source: |
Antioxidants, Vol 11, Iss 7, p 1361 (2022) |
| Publisher Information: |
MDPI AG, 2022. |
| Publication Year: |
2022 |
| Collection: |
LCC:Therapeutics. Pharmacology |
| Subject Terms: |
EMPF2, mitochondrial calcium, mitochondrial fission factor, reactive oxygen species, stem cells from human exfoliated deciduous teeth, Therapeutics. Pharmacology, RM1-950 |
| More Details: |
Mitochondrial fission factor (MFF) is an adapter that targets dynamin-related protein 1 from the cytosol to the mitochondria for fission. Loss-of-function MFF mutations cause encephalopathy due to defective mitochondrial and peroxisomal fission 2 (EMPF2). To elucidate the molecular mechanisms that were involved, we analyzed the functional effects of MFF depletion in deciduous teeth-derived dental pulp stem cells differentiating into dopaminergic neurons (DNs). When treated with MFF-targeting small interfering RNA, DNs showed impaired neurite outgrowth and reduced mitochondrial signals in neurites harboring elongated mitochondria. MFF silencing also caused mitochondrial Ca2+ accumulation through accelerated Ca2+ influx from the endoplasmic reticulum (ER) via the inositol 1,4,5-trisphosphate receptor. Mitochondrial Ca2+ overload led DNs to produce excessive reactive oxygen species (ROS), and downregulated peroxisome proliferator-activated receptor-gamma co-activator-1 alpha (PGC-1α). MFF was co-immunoprecipitated with voltage-dependent anion channel 1, an essential component of the ER-mitochondrial Ca2+ transport system. Folic acid supplementation normalized ROS levels, PGC-1α mediated mitochondrial biogenesis, and neurite outgrowth in MFF depleted DNs, without affecting their mitochondrial morphology or Ca2+ levels. We propose that MFF negatively regulates the mitochondrial Ca2+ influx from the ER. MFF-insufficiency recapitulated the EMPF2 neuropathology with increased oxidative stress and suppressed mitochondrial biogenesis. ROS and mitochondrial biogenesis might be potential therapeutic targets for EMPF2. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2076-3921 |
| Relation: |
https://www.mdpi.com/2076-3921/11/7/1361; https://doaj.org/toc/2076-3921 |
| DOI: |
10.3390/antiox11071361 |
| Access URL: |
https://doaj.org/article/96e5c42f76be49d58effcdfe280cfb07 |
| Accession Number: |
edsdoj.96e5c42f76be49d58effcdfe280cfb07 |
| Database: |
Directory of Open Access Journals |
