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Bos taurus ovarian granulosa cell

ABSTRACT: Mito-nuclear crosstalk underlying ovarian aging remains elusive. Single-cell transcriptomics of aged ovaries identified senescent signatures including dysregulated mitochondrial metabolism, disturbed histone modification and enriched SASP. We demonstrated that impaired SIRT5-mediated desuccinylation drives ovarian aging. As a major substrate of SIRT5 in the TCA cycle, SUCLG2 is regulated by desuccinylation at K93 and K101, which enhances its stability and activity to rescue mitochondrial dysfunction. Conversely, SUCLG2 hypersuccinylation leads to acetyl-CoA accumulation, increases nuclear H4K8ac and upregulates metabolic genes to compensate for energy deficiency. In vivo experiments showed excess acetyl-CoA accelerates ovarian aging, while a SUCLG2 desuccinylation mutant alleviates this defect. This study reveals the molecular basis of ovarian aging and highlights the SIRT5-SUCLG2 axis as a promising therapeutic target.

INSTRUMENT(S):

ORGANISM(S): Bos Taurus (bovine)

SUBMITTER: Dejun Xu

LAB HEAD: Dejun Xu

PROVIDER: PXD079679 | Pride | 2026-07-17

REPOSITORIES: Pride

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			Action	DRS
	XA00287DA_Control_Slot1-43_1_2375.d.zip	Other
	XA00287DA_SIRT5_Slot1-44_1_2377.d.zip	Other
	checksum.txt	Txt
	result.zip	Other

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Project description:Cytosolic acetyl-coenzyme A is a precursor for many biotechnologically relevant compounds produced by Saccharomyces cerevisiae. In this yeast, cytosolic acetyl-CoA synthesis and growth strictly depend on expression of either the Acs1 or Acs2 isoenzyme of acetyl-CoA synthetase (ACS). Since hydrolysis of ATP to AMP and pyrophosphate in the ACS reaction constrains maximum yields of acetyl-CoA-derived products, this study explores replacement of ACS by two ATP-independent pathways for acetyl-CoA synthesis. After evaluating expression of different bacterial genes encoding acetylating acetaldehyde dehydrogenase (A-ALD) and pyruvate-formate lyase (PFL), acs1M-NM-^T acs2M-NM-^T S. cerevisiae strains were constructed in which A-ALD or PFL successfully replaced ACS. In A-ALD-dependent strains, aerobic growth rates of up to 0.27 h-1 were observed, while anaerobic growth rates of PFL-dependent S. cerevisiae (0.21 h-1) were stoichiometrically coupled to formate production. In glucose-limited chemostat cultures, intracellular metabolite analysis did not reveal major differences between A-ALD-dependent and reference strains. However, biomass yields on glucose of A-ALD- and PFL-dependent strains were lower than those of the reference strain. Transcriptome analysis suggested that reduced biomass yields were caused by acetaldehyde and formate in A-ALD- and PFL-dependent strains, respectively. Transcript profiles also indicated that a previously proposed role of Acs2 in histone acetylation is probably linked to cytosolic acetyl-CoA levels rather than to direct involvement of Acs2 in histone acetylation. While, for the first time, demonstrating that yeast ACS can be fully replaced by alternative reactions, this study demonstrates that further modifications are needed to achieve optimal in vivo efficiencies of the supply of acetyl-CoA as product precursor. To investigate the impact of introduced changes in native pathway of cytosolic acetyl-CoA formation in S. cerevisiae, a DNA microarray-based transcriptome analysis was performed on aerobic or anaerobic, glucose-limited chemostat cultures.

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Bos taurus ovarian granulosa cell

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