Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression
Abstract
:1. Introduction
2. Results
2.1. Transcriptome Sequencing and Age-Related Changes
2.2. Mutation-Related Transcriptome Changes in 19-Month-Old Animals
2.3. Mutation-Related Metabolic Changes in 19-Month-Old Animals
3. Discussion
4. Materials and Methods
4.1. Animals
4.2. RNA Extraction
4.3. cDNA Library Preparation and Sequencing
4.4. Transcriptome Data Analysis
4.5. qRT-PCR
4.6. Metabolome Analysis
4.7. Database Submission
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene Name | Fold Change | p-Value | |
---|---|---|---|
Glycolysis | |||
hexokinase 1 | Hk1 | 1.07 | 2.09 × 10−2 |
hexokinase 3 | Hk3 | 0.79 | 2.41 × 10−2 |
phosphofructokinase, liver, B-type | Pfkl | 1.09 | 5.27 × 10−3 |
phosphofructokinase, muscle | Pfkm | 1.08 | 1.22 × 10−2 |
triosephosphate isomerase 1 | Tpi1 | 1.09 | 6.05 × 10−3 |
phosphoglycerate kinase 1 | Pgk1 | 1.08 | 1.24 × 10−2 |
phosphoglycerate mutase 1 | Pgam1 | 1.10 | 9.78 × 10−3 |
enolase 2 | Eno2 | 1.12 | 2.63 × 10−4 |
pyruvate kinase, muscle | Pkm | 1.10 | 3.32 × 10−3 |
lactate dehydrogenase B | Ldhb | 1.07 | 2.75 × 10−2 |
Mitochondrial transporters | |||
mitochondrial pyruvate carrier 1 | Mpc1 | 1.19 | 2.42 × 10−5 |
mitochondrial pyruvate carrier 2 | Mpc2 | 1.08 | 3.99 × 10−2 |
solute carrier family 25 member 4 (mitochondrial ATP/ADP translocator) | Slc25a4 | 1.10 | 2.70 × 10−3 |
solute carrier family 25 member 12 (mitochondrial aspartate/glutamate antiporter Aralar) | Slc25a12 | 1.07 | 2.54 × 10−2 |
TCA and related processes | |||
dihydrolipoamide S-acetyltransferase (component of pyruvate dehydrogenase complex) | Dlat | 1.07 | 4.00 × 10−2 |
dihydrolipoamide dehydrogenase | Dld | 1.16 | 1.17 × 10−5 |
pyruvate dehyrogenase phosphatase catalytic subunit 1 | Pdp1 | 1.08 | 1.73 × 10−2 |
isocitrate dehydrogenase 3 (NAD+), gamma | Idh3g | 1.10 | 4.79 × 10−3 |
isocitrate dehydrogenase 3 (NAD+) beta | Idh3b | 1.07 | 2.53 × 10−2 |
malate dehydrogenase 1, NAD (cytosolic) | Mdh1 | 1.13 | 1.42 × 10−4 |
malate dehydrogenase 2, NAD (mitochondrial) | Mdh2 | 1.08 | 8.42 × 10−3 |
oxoglutarate dehydrogenase-like (mitochondrial) | Ogdhl | 1.10 | 1.56 × 10−3 |
succinate-Coenzyme A ligase, ADP-forming, beta subunit | Sucla2 | 1.07 | 2.56 × 10−2 |
succinate dehydrogenase complex, subunit B | Sdhb | 1.07 | 3.86 × 10−2 |
fumarate hydratase 1 | Fh1 | 1.08 | 3.16 × 10−2 |
glutamate oxaloacetate transaminase 2 (mitochondrial) | Got2 | 1.13 | 1.05 × 10−4 |
ATP citrate lyase | Acly | 1.09 | 4.38 × 10−3 |
acetyl-Coenzyme A carboxylase beta | Acacb | 1.23 | 4.84 × 10−5 |
Fatty acid transport and degradation | |||
carnitine palmitoyltransferase 1a, liver | Cpt1a | 0.90 | 2.77 × 10−3 |
acyl-CoA synthetase family member 2 | Acsf2 | 0.80 | 1.61 × 10−3 |
acyl-CoA synthetase short-chain family member 3 | Acss3 | 0.82 | 3.30 × 10−2 |
acyl-CoA synthetase short-chain family member 1 | Acss1 | 0.91 | 4.41 × 10−2 |
2,4-dienoyl CoA reductase 1, mitochondrial | Decr1 | 0.89 | 1.20 × 10−2 |
Glutathione metabolism and ROS | |||
glutathione S-transferase, mu7 | Gstm7 | 1.15 | 2.43 × 10−2 |
glutathione peroxidase 4 | Gpx4 | 1.07 | 3.82 × 10−2 |
superoxide dismutase 1, cytosolic | Sod1 | 1.07 | 3.84 × 10−2 |
peroxiredoxin 5 | Prdx5 | 1.17 | 1.32 × 10−6 |
peroxiredoxin 2 | Prdx2 | 1.09 | 5.83 × 10−3 |
Metabolite | Fold Change (19M MRPS5V338Y/V338Y vs. MRPS5WT/WT) | p-Value (Welch’s t-Test) |
---|---|---|
TCA | ||
alpha-ketoglutarate | 1.19 | 0.003 |
isocitrate | 1.69 | 0.004 |
acetyl CoA | 1.38 | 0.014 |
FA degradation | ||
deoxycarnitine | 1.21 | 0.096 |
acetylcarnitine | 1.38 | 0.028 |
oleoylcarnitine | 1.80 | 0.056 |
palmitoylcarnitine | 1.60 | 0.098 |
Ascorbate metabolism | ||
dehydroascorbate | 1.21 | 0.050 |
ascorbate (Vitamin C) | 0.44 | 0.062 |
Glutathione metabolism | ||
glutathione, oxidized (GSSG) | 1.92 | 0.003 |
glutathione, reduced (GSH) | 1.39 | 0.048 |
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Shcherbakov, D.; Juskeviciene, R.; Cortés Sanchón, A.; Brilkova, M.; Rehrauer, H.; Laczko, E.; Böttger, E.C. Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression. Int. J. Mol. Sci. 2021, 22, 2746. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052746
Shcherbakov D, Juskeviciene R, Cortés Sanchón A, Brilkova M, Rehrauer H, Laczko E, Böttger EC. Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression. International Journal of Molecular Sciences. 2021; 22(5):2746. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052746
Chicago/Turabian StyleShcherbakov, Dimitri, Reda Juskeviciene, Adrián Cortés Sanchón, Margarita Brilkova, Hubert Rehrauer, Endre Laczko, and Erik C. Böttger. 2021. "Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression" International Journal of Molecular Sciences 22, no. 5: 2746. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052746