PXD011579

PXD011579 is an original dataset announced via ProteomeXchange.

Title	Metformin treatment initiated late in life impairs systemic energy homeostasis and reduces life span by acting in synergy with age-linked mitochondrial dysfunction
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.
HostingRepository	PRIDE
AnnounceDate	2020-09-21
AnnouncementXML	Submission_2020-09-21_00:00:01.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joanna Kirkpatrick
SpeciesList	scientific name: Caenorhabditis elegans; NCBI TaxID: 6239;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2018-11-05 02:31:21	ID requested
⏵ 1	2020-09-21 00:00:01	announced

Dataset with its publication pending

submitter keyword: Metformin, mitochondrial dysfunction, energy homeostasis, ageing

Maria Ermolaeva
contact affiliation	Group Leader Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) Beutenbergstrasse 11 07745 Jena, Germany
contact email	Maria.Ermolaeva@leibniz-fli.de
lab head
Joanna Kirkpatrick
contact affiliation	Leibniz Institute on Aging - FLI
contact email	joanna.kirkpatrick@leibniz-fli.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD011579
     1. Label: PRIDE project
     2. Name: Metformin treatment initiated late in life impairs systemic energy homeostasis and reduces life span by acting in synergy with age-linked mitochondrial dysfunction