Journal article
Lipid peroxidation products induce carbonyl stress, mitochondrial dysfunction, and cellular senescence in human and murine cells
Aging cell, Vol.24(1), e14367
01/2025
DOI: 10.1111/acel.14367
PMCID: PMC11709094
PMID: 39394673
Abstract
Abstract Lipid enals are electrophilic products of lipid peroxidation that induce genotoxic and proteotoxic stress by covalent modification of DNA and proteins, respectively. As lipid enals accumulate to substantial amounts in visceral adipose during obesity and aging, we hypothesized that biogenic lipid enals may represent an endogenously generated, and therefore physiologically relevant, senescence inducers. To that end, we identified that 4‐hydroxynonenal (4‐HNE), 4‐hydroxyhexenal (4‐HHE) or 4‐oxo‐2‐nonenal (4‐ONE) initiate the cellular senescence program of IMR90 fibroblasts and murine adipose stem cells. In such cells, lipid enals induced accumulation of γH2AX foci, increased p53 signaling, enhanced expression of p21 Cip1 , and upregulated the expression and secretion of numerous cytokines, chemokines, and regulatory factors independently from NF‐κB activation. Concomitantly, lipid enal treatment resulted in covalent modification of mitochondrial proteins, reduced mitochondrial spare respiratory capacity, altered nucleotide pools, and increased the phosphorylation of AMP kinase. Lipid‐induced senescent cells upregulated BCL2L1 (Bcl‐xL) and BCL2L2 (Bcl‐w). and were resistant to apoptosis while pharmacologic inhibition of BAX/BAK macropores attenuated lipid‐induced senescence. In situ, the 4‐HNE scavenger L‐carnosine ameliorated the development of the cellular senescence, while in visceral fat of obese C57BL/6J mice, L‐carnosine reduced the abundance of 4‐HNE‐modified proteins and blunted the expression of senescence biomarkers CDKN1A (p21 Cip1 ), PLAUR , BCL2L1 , and BCL2L2. Taken together, the results suggest that lipid enals are endogenous regulators of cellular senescence and that biogenic lipid‐induced senescence (BLIS) may represent a mechanistic link between oxidative stress and age‐dependent pathologies.
Details
- Title: Subtitle
- Lipid peroxidation products induce carbonyl stress, mitochondrial dysfunction, and cellular senescence in human and murine cells
- Creators
- T. Blake Monroe - University of MinnesotaAnn V. Hertzel - University of MinnesotaDeborah M. Dickey - University of MinnesotaThomas Hagen - University of MinnesotaSimon Vergara Santibanez - University of MinnesotaIslam A. Berdaweel - University of IowaCatherine Halley - University of MinnesotaPatrycja Puchalska - University of MinnesotaEthan J. Anderson - University of IowaChristina D. Camell - University of MinnesotaPaul D. Robbins - University of MinnesotaDavid A. Bernlohr - University of Minnesota
- Resource Type
- Journal article
- Publication Details
- Aging cell, Vol.24(1), e14367
- DOI
- 10.1111/acel.14367
- PMID
- 39394673
- PMCID
- PMC11709094
- NLM abbreviation
- Aging Cell
- ISSN
- 1474-9718
- eISSN
- 1474-9726
- Publisher
- WILEY
- Grant note
- American Heart Association: 20SFRN35200003 National Institutes of Health: NIH P01 AG062413, NIH R01 AG069819, NIH U54 AG079754, NIHT32AG029796
American Heart Association, Grant/Award Number: 20SFRN35200003; National Institutes of Health, Grant/Award Number: NIH P01 AG062413, NIH R01 AG069819, NIH U54 AG079754 and NIHT32AG029796.
- Language
- English
- Electronic publication date
- 10/11/2024
- Date published
- 01/2025
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984734287802771
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