Dataset Information

α-Lipoic acid ameliorates consequences of copper overload by upregulating selenoproteins and decreasing redox misbalance

ABSTRACT: α-Lipoic acid (LA) is an essential cofactor for mitochondrial dehydrogenases and is required for cell growth, metabolic fuels production, and antioxidant defense. In vitro, LA binds copper (Cu) with high affinity, and as an endogenous membrane permeable metabolite could be advantageous in mitigating the consequences of Cu overload in human diseases. We tested this hypothesis in 3T3-L1 preadipocytes with inactivated Cu transporter Atp7a; these cells accumulate Cu and show morphologic changes and mitochondria impairment. Treatment with LA corrected the morphology of Atp7a-/- 60 cells similar to the Cu chelator bathocuproinedisulfonate (BCS) and improved mitochondria function; however, the mechanisms of LA and BCS action were different. Unlike BCS, LA did not decrease intracellular Cu, but instead increased selenium levels that were low in Atp7a-/- cells. Proteome analysis confirmed distinct cell responses to these compounds and identified upregulation of selenoproteins as the major effect of LA on preadipocytes. Upregulation of selenoproteins was associated with improved GSH:GSSG ratio in cellular compartments, which was lowered by elevated Cu, and reversal of protein oxidation. Thus, LA diminishes toxic effects of elevated Cu by improving cellular redox environment. We also show that selenium levels are decreased in tissues of Wilson disease animal model, especially in the liver, making LA an attractive candidate for supplemental treatment of this disease.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Fibroblast

DISEASE(S): Wilson Disease

SUBMITTER: Josh Smith

LAB HEAD: Svetlana Lutsenko

PROVIDER: PXD045233 | Pride | 2024-05-23

REPOSITORIES: Pride

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			Action	DRS
	230418_LutsenkoS_KS_TMTpro_NoFrac_2p_1a5ug_Separate_NormAll_.msf	Msf
	JS-E480-CS_230628_LutsenkoS_KS_DIA_S10_60pct.raw	Raw
	JS-E480-CS_230628_LutsenkoS_KS_DIA_S10_60pct_rank1.pepXML	Pepxml
	JS-E480-CS_230628_LutsenkoS_KS_DIA_S10_60pct_rank2.pepXML	Pepxml
	JS-E480-CS_230628_LutsenkoS_KS_DIA_S10_60pct_rank3.pepXML	Pepxml

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α-lipoic acid ameliorates consequences of copper overload by up-regulating selenoproteins and decreasing redox misbalance.

Kabin Ekaterina E Dong Yixuan Y Roy Shubhrajit S Smirnova Julia J Smith Joshua W JW Ralle Martina M Summers Kelly K Yang Haojun H Dev Som S Wang Yu Y Devenney Benjamin B Cole Robert N RN Palumaa Peep P Lutsenko Svetlana S

Proceedings of the National Academy of Sciences of the United States of America 20230926 40

α-lipoic acid (LA) is an essential cofactor for mitochondrial dehydrogenases and is required for cell growth, metabolic fuel production, and antioxidant defense. In vitro, LA binds copper (Cu) with high affinity and as an endogenous membrane permeable metabolite could be advantageous in mitigating the consequences of Cu overload in human diseases. We tested this hypothesis in 3T3-L1 preadipocytes with inactivated Cu transporter Atp7a; these cells accumulate Cu and show morphologic changes and mi ...[more]

PMID: 37751556

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