Dataset Information

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

ABSTRACT: Redox proteomic data from the heart of young mice, old mice, or mice treated with SS31. Quantification of protein-S-glutathionylation was performed using an established redox proteomics workflow. LC-MS/MS raw data were searched with MS-GF+ against the mouse protein sequence database from the Uniprot.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Wei-Jun Qian

PROVIDER: MSV000085329 | MassIVE | Thu Apr 23 13:16:00 BST 2020

REPOSITORIES: MassIVE

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Publications

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice.

Chiao Ying Ann YA Zhang Huiliang H Sweetwyne Mariya M Whitson Jeremy J Ting Ying Sonia YS Basisty Nathan N Pino Lindsay K LK Quarles Ellen E Nguyen Ngoc-Han NH Campbell Matthew D MD Zhang Tong T Gaffrey Matthew J MJ Merrihew Gennifer G Wang Lu L Yue Yongping Y Duan Dongsheng D Granzier Henk L HL Szeto Hazel H HH Qian Wei-Jun WJ Marcinek David D MacCoss Michael J MJ Rabinovitch Peter P

eLife 20200710

Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans. We show here that 8-week treatment of old mice with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit. SS-31 normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice, accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. Improved diastolic function was concorda ...[more]

PMID: 32648542

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Project description:Metformin is a type 2 diabetes medication which extends life span across species when given from young adulthood onwards; late life effects of metformin are not well understood. Here we used C. elegans to investigate the outcome of metformin treatment initiated late in life. We found that, contrary to young age administration, old age metformin treatment interferes with energy homeostasis and shortens life span by aggravating age-associated mitochondrial dysfunction. Nematode mutants defective in mitochondrial respiration, mitochondrial biogenesis and mitochondrial quality control were highly susceptible to metformin killing already at young age while insulin receptor deficient nematodes carrying healthier mitochondria were protected from late life metformin toxicity. In the mammalian cell culture model of replicative senescence metformin killing correlated with loss of mitochondrial membrane potential and strong reduction of systemic ATP levels. Reduced ATP levels and depletion of lipid stores consistent with energy deficit were observed also in nematodes following late life metformin treatment. At the molecular level young animals responded to metformin by inducing adaptive stress responses and longevity-assurance pathways while old nematodes demonstrated a protein expression signature consistent with lipid turnover and energy deficit. Ectopic ATP supplementation was sufficient to alleviate metformin toxicity in human skin fibroblasts highlighting the key contribution of energy deficit to the detrimental effect of metformin. Also, co-exposure with rapamycin, known to stabilize cellular ATP levels under conditions of mitochondrial failure, significantly reduced metformin-inflicted lethality in both cells and old animals. In summary we uncovered a novel negative synergism between metformin treatment and mitochondrial dysfunction which gains importance late in life and may limit therapeutic benefits of metformin for older patients; these side effects can partially be overcome by co-treatment with agents stabilizing cellular ATP levels such as rapamycin.

Dataset Information

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Publications

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice.

Similar Datasets

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