Age-related disruption of the proteome and acetylome in mouse hearts is associated with loss of function and attenuated by elamipretide (SS-31) and nicotinamide mononucleotide (NMN) treatment

Whitson, Jeremy; Johnson, Richard S.; Wang, Lu; Bammler, Theo K.; Imai, Shin‐ichiro; Zhang, Huiliang; Fredrickson, Jeanne; Latorre-Esteves, Elena; Bitto, Alessandro; MacCoss, Michael J.; Rabinovitch, Peter S.

doi:10.1007/s11357-022-00564-w

Cited by 13 publications

(7 citation statements)

References 20 publications

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“…While our group has used this QC framework in various stages for years, the series of case studies presented here represents the first detailed summary of our current QC process. Although we initially used DDA and spectral counting for system suitability measurements, we quickly moved on to targeted methods 71 , added internal QCs 72 , and incorporated external QCs alongside internal QCs and system suitability 73 . Additional examples of studies where this QC workflow was applied are listed on Panorama under the "Reference Information" folder.…”

Section: Discussionmentioning

confidence: 99%

“…Although we initially used DDA and spectral counting for system suitability measurements, we quickly moved on to targeted methods 71 , added internal QCs 72 , and incorporated external QCs alongside internal QCs and system suitability 73 . Additional examples of studies where this QC workflow was applied are listed on Panorama under the “Reference Information” folder.…”

Section: Discussionmentioning

confidence: 99%

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A framework for quality control in quantitative proteomics

Tsantilas,

Merrihew,

Robbins

et al. 2024

Preprint

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A thorough evaluation of the quality, reproducibility, and variability of bottom-up proteomics data is necessary at every stage of a workflow from planning to analysis. We share real-world case studies applying adaptable quality control (QC) measures to assess sample preparation, system function, and quantitative analysis. System suitability samples are repeatedly measured longitudinally with targeted methods, and we share examples where they are used on three instrument platforms to identify severe system failures and track function over months to years. Internal QCs incorporated at protein and peptide-level allow our team to assess sample preparation issues and to differentiate system failures from sample-specific issues. External QC samples prepared alongside our experimental samples are used to verify the consistency and quantitative potential of our results during batch correction and normalization before assessing biological phenotypes. We combine these controls with rapid analysis using Skyline, longitudinal QC metrics using AutoQC, and server-based data deposition using PanoramaWeb. We propose that this integrated approach to QC be used as a starting point for groups to facilitate rapid quality control assessment to ensure that valuable instrument time is used to collect the best quality data possible.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A framework for quality control in quantitative proteomics

Tsantilas,

Merrihew,

Robbins

et al. 2024

Preprint

Self Cite

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“…Similarly, SS-31 improved the aging phenotype in different organs and tissues. Treatment with elamipretide (SS-31) for 8 weeks restored reduced diastolic function in treated old mice, whereas it had no effect in treated young mice [ 35 ]. Furthermore, the beneficial effects of SS-31/elamipretide on skeletal muscle function [ 36 , 37 ] and in angiotensin II-induced cardiomyopathy [ 38 ] were reported by different groups.…”

Section: Discussionmentioning

confidence: 99%

Targeting mitochondria in the aged cerebral vasculature with SS-31, a proteomic study of brain microvessels

et al. 2023

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Cognitive impairment and dementias during aging such as Alzheimer’s disease are linked to functional decline and structural alterations of the brain microvasculature. Although mechanisms leading to microvascular changes during aging are not clear, loss of mitochondria, and reduced efficiency of remaining mitochondria appear to play a major role. Pharmacological agents, such as SS-31, which target mitochondria have been shown to be effective during aging and diseases; however, the benefit to mitochondrial- and non-mitochondrial proteins in the brain microvasculature has not been examined. We tested whether attenuation of aging-associated changes in the brain microvascular proteome via targeting mitochondria represents a therapeutic option for the aging brain. We used aged male (> 18 months) C57Bl6/J mice treated with a mitochondria-targeted tetrapeptide, SS-31, or vehicle saline. Cerebral blood flow (CBF) was determined using laser speckle imaging during a 2-week treatment period. Then, isolated cortical microvessels (MVs) composed of end arterioles, capillaries, and venules were used for Orbitrap Eclipse Tribrid mass spectrometry. CBF was similar among the groups, whereas bioinformatic analysis revealed substantial differences in protein abundance of cortical MVs between SS-31 and vehicle. We identified 6267 proteins, of which 12% were mitochondria-associated. Of this 12%, 107 were significantly differentially expressed and were associated with oxidative phosphorylation, metabolism, the antioxidant defense system, or mitochondrial dynamics. Administration of SS-31 affected many non-mitochondrial proteins. Our findings suggest that mitochondria in the microvasculature represent a therapeutic target in the aging brain, and widespread changes in the proteome may underlie the rejuvenating actions of SS-31 in aging.

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“…Acetylome can also be a target for therapy development, such as using drugs that modulate the activity of acetyltransferases or deacetylases, which are enzymes that add or remove acetyl groups from proteins. For example, elamipretide and nicotinamide mononucleotide are mitochondrial-targeted drugs that can restore the abundance and acetylation of proteins that are disrupted by aging in mouse hearts [ 57 ].…”

Section: Main Textmentioning

confidence: 99%

Multi-Omics Integration for the Design of Novel Therapies and the Identification of Novel Biomarkers

Ivanisevic,

Sewduth

2023

Proteomes

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Multi-omics is a cutting-edge approach that combines data from different biomolecular levels, such as DNA, RNA, proteins, metabolites, and epigenetic marks, to obtain a holistic view of how living systems work and interact. Multi-omics has been used for various purposes in biomedical research, such as identifying new diseases, discovering new drugs, personalizing treatments, and optimizing therapies. This review summarizes the latest progress and challenges of multi-omics for designing new treatments for human diseases, focusing on how to integrate and analyze multiple proteome data and examples of how to use multi-proteomics data to identify new drug targets. We also discussed the future directions and opportunities of multi-omics for developing innovative and effective therapies by deciphering proteome complexity.

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Age-related disruption of the proteome and acetylome in mouse hearts is associated with loss of function and attenuated by elamipretide (SS-31) and nicotinamide mononucleotide (NMN) treatment

Cited by 13 publications

References 20 publications

A framework for quality control in quantitative proteomics

A framework for quality control in quantitative proteomics

Targeting mitochondria in the aged cerebral vasculature with SS-31, a proteomic study of brain microvessels

Multi-Omics Integration for the Design of Novel Therapies and the Identification of Novel Biomarkers

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