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other·preclinical research, biomedical research, neurology, geriatrics, cardiology·PMC10643806

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

GeroScience · 7 authors, 3 centres

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TL;DR

Aged male C57Bl6/J mice were treated for 2 weeks with the mitochondria-targeted peptide SS-31 or vehicle, and isolated cortical microvessels were analyzed by mass spectrometry-based proteomics. SS-31 produced widespread beneficial proteomic changes in both mitochondrial and non-mitochondrial proteins, despite no detectable difference in baseline cerebral blood flow.

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Aged male C57Bl6/J mice (>18 months) were treated with SS-31 or vehicle saline for 2 weeks, after which cortical microvessels were isolated and analyzed using Orbitrap Eclipse Tribrid mass spectrometry with TMT 10-plex labeling. Cerebral blood flow measured by laser speckle imaging was similar between groups. SS-31 significantly increased Sod1 but not Sod2, and decreased Nos2 (iNOS) protein abundance. Gene set enrichment analysis revealed upregulation of glucose metabolism, glycolysis, and gluconeogenesis proteins in the treatment group. Findings suggest mitochondria in the brain microvasculature represent a viable therapeutic target in aging, though direct human relevance remains indirect.

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other

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preclinical research

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AI pipeline

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100% · A

ORIGINAL PAPER

PMC10643806

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

GeroScience

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ABSTRACT

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.

CITATION EXPORT

Abigail Seman, Partha K. Chandra, Stephanie D. Byrum et al.. Targeting mitochondria in the aged cerebral vasculature with SS-31, a proteomic study of brain microvessels. GeroScience. (2023). https://doi.org/10.1007/s11357-023-00845-y

AUTHORS

7 · 3 CENTRES

Abigail Seman, Partha K. Chandra, Stephanie D. Byrum, Samuel G. Mackintosh, Allen J. Gies, David W. Busija, Ibolya Rutkai

1grid.265219.b0000 0001 2217 8588Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112 USA
2https://ror.org/04vmvtb21grid.265219.b0000 0001 2217 8588Tulane Brain Institute, Tulane University, 200 Flower Hall, New Orleans, LA 70118 USA
3https://ror.org/00xcryt71grid.241054.60000 0004 4687 1637Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205 USA