hrvatski jezikClear Cookie - decide language by browser settings

Gene Expression Profiling Reveals Fundamental Sex-Specific Differences in SIRT3-Mediated Redox and Metabolic Signaling in Mouse Embryonic Fibroblasts

Belužić, Robert; Šimunić, Ena; Škrinjar, Iva; Pinterić, Marija; Popović Hadžija, Marijana; Balog, Tihomir; Sobočanec, Sandra (2024) Gene Expression Profiling Reveals Fundamental Sex-Specific Differences in SIRT3-Mediated Redox and Metabolic Signaling in Mouse Embryonic Fibroblasts. International Journal of Molecular Sciences, 25 (7). ISSN 1422-0067

[img] PDF - Published Version - article
Available under License Creative Commons Attribution.

Download (3MB)


Sirt-3 is an important regulator of mitochondrial function and cellular energy homeostasis, whose function is associated with aging and various pathologies such as Alzheimer’s disease, Parkinson’s disease, cardiovascular diseases, and cancers. Many of these conditions show differences in incidence, onset, and progression between the sexes. In search of hormone-independent, sex-specific roles of Sirt-3, we performed mRNA sequencing in male and female Sirt-3 WT and KO mouse embryonic fibroblasts (MEFs). The aim of this study was to investigate the sex-specific cellular responses to the loss of Sirt-3. By comparing WT and KO MEF of both sexes, the differences in global gene expression patterns as well as in metabolic and stress responses associated with the loss of Sirt-3 have been elucidated. Significant differences in the activities of basal metabolic pathways were found both between genotypes and between sexes. In-depth pathway analysis of metabolic pathways revealed several important sex-specific phenomena. Male cells mount an adaptive Hif-1a response, shifting their metabolism toward glycolysis and energy production from fatty acids. Furthermore, the loss of Sirt-3 in male MEFs leads to mitochondrial and endoplasmic reticulum stress. Since Sirt-3 knock-out is permanent, male cells are forced to function in a state of persistent oxidative and metabolic stress. Female MEFs are able to at least partially compensate for the loss of Sirt-3 by a higher expression of antioxidant enzymes. The activation of neither Hif-1a, mitochondrial stress response, nor oxidative stress response was observed in female cells lacking Sirt-3. These findings emphasize the sex-specific role of Sirt-3, which should be considered in future research.

Item Type: Article
Uncontrolled Keywords: Sirtuin 3; sex differences; mouse embryonic fibroblasts; Hif-1α; integrated stress response; unfolded protein response
Subjects: NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
Divisions: Division of Molecular Medicine
Project titleProject leaderProject codeProject type
Istraživanje spolno specifičnih metaboličkih učinaka Sirtuina 3 kod bolesti povezanih s pretilošću – Obese SirtSandra SobočanecHRZZ-IP-2022-10-4806Znanstveno-istraživački projekti
Depositing User: Sandra Sobočanec
Date Deposited: 04 Apr 2024 09:00
DOI: 10.3390/ijms25073868

Actions (login required)

View Item View Item


Downloads per month over past year

Increase Font
Decrease Font
Dyslexic Font