Differential Susceptibility of Retinal Neurons to the Loss of Mitochondrial Biogenesis Factor Nrf1
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animal Breeding
2.2. Immunohistochemistry
2.3. Photopic Electroretinography
2.4. RNA-Sequencing Analysis
2.5. Quantitative Reverse Transcriptase PCR
2.6. Terminal Deoxynucleotidyl Transferase dUTP Nick-End Labeling (TUNEL) Assay
2.7. Statistical Analysis
3. Results
3.1. Progressive Degeneration in Nrf1-Deficient Cone Photoreceptors
3.2. Slow and Progressive Reduction of Nrf1-Depleted ipRGC
3.3. Highly Sensitive Type 2 and 6 Cone Bipolar Cells to Nrf1 Deletion
3.4. The Most Sensitive Genes in Nrf1-Deficient Rod Photoreceptors
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene Name | Description | Log2 Fold Change (Nrf1f/f;RhoiCre/Nrf1f/+) | Adjusted p Value |
---|---|---|---|
Ccdc87 | coiled-coil domain containing 87 | −1.6234 | 5.89 × 10−36 |
Rnf207 | ring finger protein 207 | −1.3834 | 1.10 × 10−44 |
AI429214 | expressed sequence AI429214 | −1.3369 | 6.84 × 10−24 |
C030017K20Rik | RIKEN cDNA C030017K20 gene | −1.2807 | 1.19 × 10−31 |
Zfp182 | zinc finger protein 182 | −1.2239 | 4.54 × 10−40 |
Tbc1d24 | TBC1 domain family member 24 | −1.2234 | 9.22 × 10−120 |
Cdc7 | cell division cycle 7 (S. cerevisiae) | −1.2132 | 4.45 × 10−43 |
Samhd1 | SAM domain and HD domain 1 | −1.139 | 2.41 × 10−82 |
Zc2hc1c | zinc finger C2HC-type containing 1C | −1.1341 | 4.26 × 10−23 |
Wdr5b | WD repeat domain 5B | −1.1292 | 8.21 × 10−26 |
Sprtn | SprT-like N-terminal domain | −1.1122 | 6.12 × 10−39 |
H2-K2 | histocompatibility 2 K region locus 2 | −1.0906 | 1.58 × 10−22 |
Shisa2 | shisa family member 2 | −1.0698 | 2.44 × 10−25 |
Mlh3 | mutL homolog 3 (E. coli) | −1.0473 | 1.15 × 10−44 |
Ankrd26 * | ankyrin repeat domain 26 | −1.0158 | 1.68 × 10−55 |
Cog6 | component of oligomeric golgi complex 6 | −1.0071 | 4.78 × 10−49 |
Zfp287 | zinc finger protein 287 | −0.99342 | 7.33 × 10−27 |
Mtg2 * | mitochondrial ribosome associated GTPase 2 | −0.97742 | 5.34 × 10−33 |
Katnal2 | katanin p60 subunit A-like 2 | −0.97416 | 3.88 × 10−34 |
Mthfsd | methenyltetrahydrofolate synthetase domain containing | −0.97072 | 8.13 × 10−31 |
Zfp791 | zinc finger protein 791 | −0.96542 | 3.25 × 10−19 |
Zfp329 | zinc finger protein 329 | −0.9606 | 4.01 × 10−54 |
Pot1b | protection of telomeres 1B | −0.95894 | 9.62 × 10−21 |
Bbs2 | Bardet-Biedl syndrome 2 (human) | −0.95414 | 1.22 × 10−63 |
Dynlrb2 | dynein light chain roadblock-type 2 | −0.94971 | 6.89 × 10−14 |
Abhd5 | abhydrolase domain containing 5 | −0.9241 | 1.01 × 10−26 |
Marveld3 | MARVEL (membrane-associating) domain containing 3 | −0.91459 | 6.08 × 10−15 |
Ccdc166 | coiled-coil domain containing 166 | −0.90586 | 1.81 × 10−31 |
Exoc8 | exocyst complex component 8 | −0.90494 | 6.33 × 10−36 |
Stk38 | serine/threonine kinase 38 | −0.89765 | 2.81 × 10−60 |
Tctex1d2 | Tctex1 domain containing 2 | −0.89357 | 9.03 × 10−14 |
Gm26572 | predicted gene 26572 | −0.88514 | 1.06 × 10−16 |
Rabif | RAB interacting factor | −0.87374 | 6.53 × 10−43 |
Dynlt1c | dynein light chain Tctex-type 1C | −0.87284 | 3.64 × 10−11 |
Spint2 | serine protease inhibitor Kunitz type 2 | −0.87063 | 2.51 × 10−43 |
Fam98a | family with sequence similarity 98 member A | −0.86343 | 2.20 × 10−35 |
Slx4 | SLX4 structure-specific endonuclease subunit homolog (S. cerevisiae) | −0.85413 | 9.39 × 10−34 |
Mtrr | 5-methyltetrahydrofolate-homocysteine methyltransferase reductase | −0.84843 | 1.96 × 10−18 |
Setd4 | SET domain containing 4 | −0.83398 | 1.40 × 10−17 |
Gcfc2 | GC-rich sequence DNA binding factor 2 | −0.83387 | 2.49 × 10−15 |
Sox12 | SRY (sex determining region Y)-box 12 | −0.82933 | 7.00 × 10−21 |
Sbf2 | SET binding factor 2 | −0.82821 | 2.80 × 10−50 |
Nubp1 | nucleotide binding protein 1 | −0.82325 | 3.47 × 10−19 |
Angptl6 | angiopoietin-like 6 | −0.82273 | 9.67 × 10−13 |
Mrs2 * | MRS2 magnesium homeostasis factor homolog (S. cerevisiae) | −0.81398 | 6.57 × 10−35 |
Pdrg1 | p53 and DNA damage regulated 1 | −0.79343 | 1.45 × 10−27 |
Zfyve16 | zinc finger FYVE domain containing 16 | −0.78442 | 1.04 × 10−24 |
Ints7 | integrator complex subunit 7 | −0.783 | 5.35 × 10−33 |
Shmt2 * | serine hydroxymethyltransferase 2 (mitochondrial) | −0.78075 | 2.29 × 10−29 |
Mettl22 | methyltransferase like 22 | −0.77958 | 2.18 × 10−16 |
Ccdc93 | coiled-coil domain containing 93 | −0.77053 | 2.11 × 10−27 |
Smg9 | smg-9 homolog nonsense mediated mRNA decay factor (C. elegans) | −0.76729 | 3.83 × 10−24 |
Tmem143 * | transmembrane protein 143 | −0.75985 | 4.64 × 10−20 |
Prkdc | protein kinase DNA activated catalytic polypeptide | −0.75349 | 1.45 × 10−18 |
2310061I04Rik * | RIKEN cDNA 2310061I04 gene | −0.75092 | 6.93 × 10−17 |
Pls1 | plastin 1 (I-isoform) | −0.74708 | 2.22 × 10−10 |
Nrtn | neurturin | −0.74655 | 2.40 × 10−12 |
Nr2c1 | nuclear receptor subfamily 2 group C member 1 | −0.74308 | 2.67 × 10−19 |
Hist1h1a | histone cluster 1 H1a | 0.74952 | 7.45 × 10−8 |
Gm13421 | predicted gene 13421 | 0.77879 | 2.71 × 10−14 |
Hist1h4c | histone cluster 1 H4c | 0.78665 | 1.79 × 10−8 |
Bpifb6 | BPI fold containing family B member 6 | 0.79491 | 2.04 × 10−8 |
Hist1h2be | histone cluster 1 H2be | 0.7962 | 2.31 × 10−14 |
Nhej1 | nonhomologous end-joining factor 1 | 0.80335 | 1.01 × 10−8 |
BC051142 | cDNA sequence BC051142 | 0.81214 | 1.83 ×10−10 |
Hist1h2bj | histone cluster 1 H2bj | 0.83377 | 3.03 ×10−9 |
Ska3 | spindle and kinetochore associated complex subunit 3 | 0.84721 | 1.54 ×10−9 |
Gm11961 | predicted gene 11961 | 0.87529 | 2.79 × 10−15 |
Hist1h1e | histone cluster 1 H1e | 0.93176 | 2.49 × 10−15 |
Gm9959 | predicted gene 9959 | 0.93908 | 1.03 × 10−11 |
Rbbp8 | retinoblastoma binding protein 8 | 0.97505 | 3.74 × 10−21 |
Mlf1 | myeloid leukemia factor 1 | 0.98101 | 3.09 × 10−15 |
Bcl2l12 | BCL2-like 12 (proline rich) | 0.98105 | 9.18 × 10−13 |
Gm17101 | predicted gene 17101 | 0.98366 | 7.78 × 10−13 |
Gm12480 | predicted gene 12480 | 0.98839 | 5.94 × 10−13 |
Ino80c | INO80 complex subunit C | 0.99506 | 8.83 × 10−55 |
Gm8251 | predicted gene 8251 | 1.1522 | 1.03 × 10−18 |
Dsn1 | DSN1 MIND kinetochore complex component homolog (S. cerevisiae) | 1.1532 | 1.85 × 10−18 |
Loxl4 | lysyl oxidase-like 4 | 1.2333 | 3.80 × 10−21 |
Mutyh * | mutY homolog (E. coli) | 1.2731 | 3.28 × 10−38 |
Zcwpw1 | zinc finger CW type with PWWP domain 1 | 1.4136 | 1.66 × 10−67 |
Rad51ap1 | RAD51 associated protein 1 | 1.5557 | 1.07 × 10−41 |
Cenpi | centromere protein I | 1.8589 | 4.28 × 10−52 |
Fignl1 | fidgetin-like 1 | 2.0243 | 2.37 × 10−73 |
Casc5 | cancer susceptibility candidate 5 | 2.7592 | 6.88 × 10−109 |
Gene Name | Description | Log2 Fold change (Nrf1f/f;RhoiCre/Nrf1f/+) | Adjusted p Value |
---|---|---|---|
Ankrd26 | ankyrin repeat domain-containing protein 26 | −1.0158 | 1.68 × 10−55 |
Mtg2 | mitochondrial ribosome associated GTPase 2 | −0.97742 | 5.34 × 10−33 |
Mrs2 | MRS2 magnesium homeostasis factor homolog (S. cerevisiae) | −0.81398 | 6.57 × 10−35 |
Shmt2 | serine hydroxymethyltransferase 2 (mitochondrial) | −0.78075 | 2.29 × 10−29 |
Tmem143 | transmembrane protein 143 | −0.75985 | 4.64 × 10−20 |
2310061I04Rik | RIKEN cDNA 2310061I04 gene | −0.75092 | 4.12 × 10−19 |
Fastkd3 | FAST kinase domains 3 | −0.73257 | 6.15 × 10−12 |
Pstk | phosphoseryl tRNA kinase | −0.73031 | 1.28 × 10−16 |
Alas1 | aminolevulinic acid synthase 1 | −0.70115 | 9.42 × 10−25 |
Hsdl2 | hydroxysteroid dehydrogenase like 2 | −0.59599 | 1.75 × 10−20 |
D2hgdh | D2 hydroxyglutarate dehydrogenase | −0.58842 | 1.56 × 10−11 |
Sdr39u1 | short chain dehydrogenase/reductase family 39U member 1 | −0.55177 | 1.20 × 10−14 |
Sdha | succinate dehydrogenase complex subunit A flavoprotein (Fp) | −0.54497 | 5.27 × 10−32 |
Cecr5 | cat eye syndrome chromosome region candidate 5 | −0.53991 | 1.65 × 10−11 |
Slc25a13 | solute carrier family 25 (mitochondrial carrier adenine nucleotide translocator) member 13 | −0.53462 | 4.91 × 10−4 |
Acad10 | acyl Coenzyme A dehydrogenase family member 10 | −0.53414 | 2.61 × 10−6 |
Pccb | propionyl Coenzyme A carboxylase beta polypeptide | −0.52005 | 2.09 ×10−15 |
Exog | endo/exonuclease (5′-3′) endonuclease G-like | −0.51228 | 1.76 × 10−9 |
Ide | insulin degrading enzyme | −0.50673 | 1.97 × 10−22 |
Mcat | malonyl CoA:ACP acyltransferase (mitochondrial) | −0.48803 | 1.60 × 10−7 |
Afg3l1 | AFG3-like AAA ATPase 1 | −0.48699 | 6.23 × 10−16 |
2810006K23Rik | RIKEN cDNA 2810006K23 gene | −0.47985 | 2.65 × 10−7 |
Vars2 | valyl-tRNA synthetase 2 mitochondrial (putative) | −0.45605 | 9.55 × 10−7 |
Mtpap | mitochondrial poly(A)_polymerase | −0.45337 | 1.37 × 10−5 |
Dna2 | DNA replication helicase 2 homolog (yeast) | −0.44603 | 0.003128 |
Mrpl49 | mitochondrial ribosomal protein L49 | −0.43346 | 1.64 × 10−8 |
Nfu1 | NFU1 iron sulfur cluster scaffold homolog (S. cerevisiae) | −0.42766 | 7.19 × 10−9 |
Rpusd3 | RNA pseudouridylate synthase domain containing 3 | −0.41583 | 1.73 × 10−4 |
Abcb10 | ATP-binding cassette subfamily B (MDR/TAP) member 10 | −0.41548 | 3.37 × 10−12 |
Ppa2 | pyrophosphatase (inorganic) 2 | −0.40886 | 9.23 × 10−6 |
Bphl | biphenyl hydrolase like (serine hydrolase breast epithelial mucin associated antigen) | −0.39912 | 9.78 × 10−4 |
Dhrs7b | dehydrogenase/reductase (SDR family) member 7B | −0.39831 | 3.88 × 10−6 |
Cisd1 | CDGSH iron sulfur domain 1 | −0.3853 | 5.47 × 10−6 |
Stx17 | syntaxin 17 | −0.38146 | 4.69 × 10−7 |
Gpi1 | glucose phosphate isomerase 1 | −0.35742 | 2.27 × 10−6 |
Ndufa8 | NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 8 | −0.34492 | 2.18 × 10−4 |
Acaa1a | acetyl-Coenzyme A acyltransferase 1A | −0.33944 | 2.45 × 10−9 |
Idh3a | isocitrate dehydrogenase 3 (NAD+) alpha | −0.32204 | 5.08 × 10−9 |
Iba57 | IBA57 iron sulfur cluster assembly homolog (S. cerevisiae) | 0.33473 | 2.31 × 10−4 |
Tha1 | threonine aldolase 1 | 0.34796 | 4.24 × 10−3 |
Amacr | alpha methylacyl CoA racemase | 0.36987 | 1.82 × 10−3 |
Aldh1l2 | aldehyde dehydrogenase 1 family member L2 | 0.37356 | 3.79 × 10−3 |
Tfb1m | transcription factor B1 mitochondrial | 0.37658 | 4.31 × 10−3 |
Mrpl54 | mitochondrial ribosomal protein L54 | 0.38391 | 2.29 × 10−4 |
Mrpl36 | mitochondrial ribosomal protein L36 | 0.41616 | 9.30 × 10−5 |
Nucb2 | nucleobindin 2 | 0.48404 | 4.16 × 10−16 |
Sars2 | seryl-aminoacyl-tRNA synthetase 2 | 0.54314 | 2.87 × 10−10 |
Ephx2 | epoxide hydrolase 2 cytoplasmic | 0.56004 | 1.71 × 10−14 |
Ccdc51 | coiled-coil domain containing 51 | 0.57846 | 1.49 × 10−7 |
Ccdc127 | coiled-coil domain containing 127 | 0.58535 | 1.02 × 10−22 |
Rpl10a | ribosomal protein L10A | 0.64403 | 1.49 × 10−42 |
Mutyh | mutY homolog (E. coli) | 1.2731 | 3.28 × 10−38 |
GO Biological Process ID | Number of Focused Genes | Fold Enrichment | Raw p-Value | FDR | Gene Name |
---|---|---|---|---|---|
regulation of double-strand break repair (GO:2000779) | 6 | 18.07 | 1.35 × 10−6 | 3.05 × 10−3 | Pot1b, Rad51ap1, Fignl1, Rbbp8, Zcwpw1, Prkdc |
double-strand break repair via homologous recombination (GO:0000724) | 5 | 16.42 | 1.69 × 10−5 | 1.91 × 10−2 | Cdc7, Slx4, Samhd1, Rad51ap1, Rbbp8 |
regulation of DNA recombination (GO:0000018) | 6 | 15.04 | 3.75 × 10−6 | 6.57 × 10−3 | Pot1b, Rad51ap1, Fignl1, Rbbp8, Zcwpw1, Hist1h1a |
positive regulation of DNA repair (GO:0045739) | 5 | 14.79 | 2.74 × 10−5 | 2.70 × 10−2 | Rad51ap1, Rbbp8, Zcwpw1, Ino80c, Prkdc |
Gene Name | Description | Fold Change (Nrf1f/f;RhoiCre/Nrf1f/+) | Adjusted p Value |
---|---|---|---|
Hk1 | Hexokinase 1 | 1.24 | 5.35 × 10−10 |
Gpi1 | Glucose-6-phsphate isomerase 1 | 0.78 | 2.27 × 10−6 |
Pgam1 | Phosphoglycerate mutase 1 | 0.81 | 1.57 × 10−4 |
Pgm2 | Phosphoglucomutase-2 | 0.80 | 1.34 × 10−3 |
Eno1 | Enolase 1, alpha non-neuron | 0.82 | 5.76 × 10−3 |
Pkm | Pyruvate kinase, muscle | 0.80 | 5.76 × 10−6 |
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Kiyama, T.; Chen, C.-K.; Zhang, A.; Mao, C.-A. Differential Susceptibility of Retinal Neurons to the Loss of Mitochondrial Biogenesis Factor Nrf1. Cells 2022, 11, 2203. https://doi.org/10.3390/cells11142203
Kiyama T, Chen C-K, Zhang A, Mao C-A. Differential Susceptibility of Retinal Neurons to the Loss of Mitochondrial Biogenesis Factor Nrf1. Cells. 2022; 11(14):2203. https://doi.org/10.3390/cells11142203
Chicago/Turabian StyleKiyama, Takae, Ching-Kang Chen, Annie Zhang, and Chai-An Mao. 2022. "Differential Susceptibility of Retinal Neurons to the Loss of Mitochondrial Biogenesis Factor Nrf1" Cells 11, no. 14: 2203. https://doi.org/10.3390/cells11142203