Mitochondrial DNA Instability Supersedes Parkin Mutations in Driving Mitochondrial Proteomic Alterations and Functional Deficits in Polg Mutator Mice
Abstract
:1. Introduction
2. Results
2.1. Liver Mitochondrial but Not Synaptosomal Protein Turnover Rates Are Affected by mtDNA Fidelity
2.2. Loss of mtDNA Fidelity Alters Dynamics of Proteins of Metabolism and Bioenergetics
2.3. Impaired mtDNA Fidelity Influences Oxidative Phosphorylation and Electron Transport Protein Expression
2.4. Influence of Parkin Expression or Activity on Proteome Dynamics in Polg Animals
2.4.1. Parkin Deficiency Reduces Turnover of Liver Mitochondrial Proteins
2.4.2. ParkinW402A Enhances Turnover of Synaptic Mitochondrial Proteins
2.5. Polg Is the Primary Driver of Altered Proteostasis and Tissue, Specifically Modified by Parkin
2.6. Parkin’s Influence on Protein Expression Is Greater in Liver Mitochondria Than Synaptosomes
2.7. Pathway Analysis Reveals Parkin Fine Tunes Polg-Driven Protein Abundance Effects
2.8. Polg Mutator Mice Exhibit Tissue-Specific Bioenergetic Capacity Impacted by Parkin Status
3. Discussion
4. Materials and Methods
4.1. Study Design
4.2. Metabolic Labeling with Heavy Leucine
4.3. Subcellular Fractionation
4.3.1. Liver Mitochondria
4.3.2. Heart Ventricular Mitochondria
4.3.3. Synaptic Terminals (Synaptosomes)
4.4. Seahorse Metabolic Flux
4.4.1. Bioenergetic Analysis of Synaptosomes
4.4.2. Bioenergetic Analysis of Liver Mitochondria
4.5. Mass Spectrometry
4.5.1. Mass Spectrometry Sample Prep
4.5.2. Mass Spectrometry Acquisition
Liquid Chromatography
Data Acquisition
4.5.3. Mass Spectrometry Analysis
Abundance
Turnover
4.6. Pathway Analysis
4.7. Western Blot Analysis
4.8. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Trease, A.J.; Totusek, S.; Lichter, E.Z.; Stauch, K.L.; Fox, H.S. Mitochondrial DNA Instability Supersedes Parkin Mutations in Driving Mitochondrial Proteomic Alterations and Functional Deficits in Polg Mutator Mice. Int. J. Mol. Sci. 2024, 25, 6441. https://doi.org/10.3390/ijms25126441
Trease AJ, Totusek S, Lichter EZ, Stauch KL, Fox HS. Mitochondrial DNA Instability Supersedes Parkin Mutations in Driving Mitochondrial Proteomic Alterations and Functional Deficits in Polg Mutator Mice. International Journal of Molecular Sciences. 2024; 25(12):6441. https://doi.org/10.3390/ijms25126441
Chicago/Turabian StyleTrease, Andrew J., Steven Totusek, Eliezer Z. Lichter, Kelly L. Stauch, and Howard S. Fox. 2024. "Mitochondrial DNA Instability Supersedes Parkin Mutations in Driving Mitochondrial Proteomic Alterations and Functional Deficits in Polg Mutator Mice" International Journal of Molecular Sciences 25, no. 12: 6441. https://doi.org/10.3390/ijms25126441