Lipid peroxidation products induce carbonyl stress, mitochondrial dysfunction, and cellular senescence in human and murine cells.

Autor:	Monroe TB; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Hertzel AV; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Dickey DM; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Hagen T; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Santibanez SV; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Berdaweel IA; Department of Pharmaceutical Sciences & Experimental Therapeutics, College of Pharmacy, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA., Halley C; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Puchalska P; Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Anderson EJ; Department of Pharmaceutical Sciences & Experimental Therapeutics, College of Pharmacy, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA., Camell CD; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.; Institute for the Biology of Aging and Metabolism, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Robbins PD; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.; Institute for the Biology of Aging and Metabolism, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Bernlohr DA; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
Jazyk:	angličtina
Zdroj:	Aging cell [Aging Cell] 2025 Jan; Vol. 24 (1), pp. e14367. Date of Electronic Publication: 2024 Oct 11.
DOI:	10.1111/acel.14367
Abstrakt:	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. (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Databáze:	MEDLINE
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