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Mitochondrial Sirt3 in Kidney Aging: Sex-Specific Links to Metabolic Homeostasis and Oxidative Stress
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Mitochondrial Sirt3 in Kidney Aging: Sex-Specific Links to Metabolic Homeostasis and Oxidative Stress
Rudjer Boskovic Institute , Zagreb , Croatia
Rudjer Boskovic Institute , Zagreb , Croatia
Rudjer Boskovic Institute , Zagreb , Croatia
Rudjer Boskovic Institute , Zagreb , Croatia
Rudjer Boskovic Institute , Zagreb , Croatia
Rudjer Boskovic Institute , Zagreb , Croatia
Rudjer Boskovic Institute , Zagreb , Croatia
Medical University of Graz , Graz , Austria
Medical University of Graz , Graz , Austria
Abstract
Purpose: Aging is a complex biological process that begins at the cellular level, disrupting energy homeostasis. This study investigated the role of Sirt3, major mitochondrial deacetylase involved in metabolic pathways, in sex-dependent changes in energy homeostasis during aging in kidney of Sirt3 WT and KO mice.
Methods: Enzymatic activity, lipid peroxidation, protein carbonylation with Western blot and metabolomic analyses were performed to assess physiological and metabolic parameters
Results: Higher Sirt3 expression in male WT mice leads to increased vulnerability to its deficiency, as reflected in the shorter lifespan of male KO mice. This is further supported by distinct metabolomic clustering in male KO mice, highlighting significant metabolic disruptions. Male-specific declines in metabolites such as creatine, phosphorylcholine, trimethylamine-N-oxide, and L-carnitine, along with reduced trifunctional multienzyme complex subunit β (HADHB) expression, point to impaired fatty acid metabolism and mitochondrial dysfunction.
Conclusions: The findings emphasize the sex-specific function of Sirt3 in regulating mitochondrial activity, energy metabolism, and oxidative stress in the murine kidney, with male mice exhibiting a greater reliance on Sirt3 for metabolic stability.
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Funding Statement
This work was supported in part by the Croatian Science Foundation [Grant number IP-2022-10-4806]. T.M. is grateful to the Austrian Science Fund (FWF) for excellence cluster 10.55776/COE14, Grants DOI 10.55776/P28854, 10.55776/I3792, 10.55776/DOC130, and 10.55776/W1226, the Austrian Research Promotion Agency (FFG) grants 864690 and 870454; the Integrative Metabolism Research Center Graz; the Austrian Infrastructure Program 2016/2017; the Styrian Government (Zukunftsfonds, doc.fund program); the City of Graz; and BioTechMed-Graz (flagship project). This project was funded in part by the FFG (www.ffg.at) and the European Union (EFRE) under grant 912192. For open access purposes, the author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission.
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