Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
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ABSTRACT:
SUBMITTER: Morgenstern M
PROVIDER: S-EPMC8664129 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND: A large variety of proteins involved in inflammation, coagulation, lipid-oxidation and lipid metabolism have been associated with high-density lipoprotein (HDL) and it is anticipated that changes in the HDL proteome have implications for the multiple functions of HDL. Here, SELDI-TOF mass spectrometry (MS) was used to study the dynamic changes of HDL protein composition in a human experimental low-dose endotoxemia model. Ten healthy men with low HDL cholesterol (0.7+/-0.1 mmol/L) and 10 men with high HDL cholesterol levels (1.9+/-0.4 mmol/L) were challenged with endotoxin (LPS) intravenously (1 ng/kg bodyweight). We previously showed that subjects with low HDL cholesterol are more susceptible to an inflammatory challenge. The current study tested the hypothesis that this discrepancy may be related to differences in the HDL proteome. RESULTS: Plasma drawn at 7 time-points over a 24 hour time period after LPS challenge was used for direct capture of HDL using antibodies against apolipoprotein A-I followed by subsequent SELDI-TOF MS profiling. Upon LPS administration, profound changes in 21 markers (adjusted p-value < 0.05) were observed in the proteome in both study groups. These changes were observed 1 hour after LPS infusion and sustained up to 24 hours, but unexpectedly were not different between the 2 study groups. Hierarchical clustering of the protein spectra at all time points of all individuals revealed 3 distinct clusters, which were largely independent of baseline HDL cholesterol levels but correlated with paraoxonase 1 activity. The acute phase protein serum amyloid A-1/2 (SAA-1/2) was clearly upregulated after LPS infusion in both groups and comprised both native and N-terminal truncated variants that were identified by two-dimensional gel electrophoresis and mass spectrometry. Individuals of one of the clusters were distinguished by a lower SAA-1/2 response after LPS challenge and a delayed time-response of the truncated variants. CONCLUSIONS: This study shows that the semi-quantitative differences in the HDL proteome as assessed by SELDI-TOF MS cannot explain why subjects with low HDL cholesterol are more susceptible to a challenge with LPS than those with high HDL cholesterol. Instead the results indicate that hierarchical clustering could be useful to predict HDL functionality in acute phase responses towards LPS.
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Project description:Mitochondria perform central functions in cellular bioenergetics, metabolism and signaling and their malfunction has been linked to numerous diseases. The available studies cover only part of the mitochondrial proteome and a separation of core mitochondrial proteins from associated fractions has not been achieved. We developed an integrative, quantitative MS-based experimental approach to define the high confidence proteome of yeast mitochondria and to identify new mitochondrial proteins. The analysis includes protein abundance under fermentable and non-fermentable growth, submitochondrial localization, single-protein analysis and subcellular classification of mitochondria-associated fractions. We identified novel mitochondrial interactors of respiratory chain supercomplexes, ATP synthase, AAA proteases, the mitochondrial contact site and cristae organizing system (MICOS) and coenzyme Q biosynthesis cluster as well as new mitochondrial proteins with dual cellular localization. The integrative proteome provides a high confidence source for the characterization of physiological and pathophysiological functions of mitochondria and their integration into the cellular environment.
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