Acetyl-CoA carboxylase maintains energetic balance for functional oogenesis

Oyundari Amartuvshin, Chi-Hung Lin, Yi-Ting Ke, Han-Jung Lee, Kreeti Kajal, Tsai-Ling Huang, Wen- Der Wang, Tsai-Ming Lu, Ling-Huei Yih, Chen-Yuan Tseng and Hwei-Jan Hsu ()
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Oyundari Amartuvshin: National Defense Medical University, Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Sciences
Chi-Hung Lin: National Defense Medical University, Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Sciences
Yi-Ting Ke: Institute of Cellular and Organismic Biology, Academia Sinica
Han-Jung Lee: Institute of Cellular and Organismic Biology, Academia Sinica
Kreeti Kajal: Institute of Cellular and Organismic Biology, Academia Sinica
Tsai-Ling Huang: National Chung Hsing University, Institute of Molecular Biology
Wen- Der Wang: Chia-Yi University, Department of Agriculture and Biotechnology
Tsai-Ming Lu: Institute of Cellular and Organismic Biology, Academia Sinica
Ling-Huei Yih: Institute of Cellular and Organismic Biology, Academia Sinica
Chen-Yuan Tseng: National Chung Hsing University, Institute of Molecular Biology
Hwei-Jan Hsu: National Defense Medical University, Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Reproduction is tightly linked to nutrient availability and metabolic homeostasis, yet how specific metabolic pathways coordinate with cellular signaling to control oogenesis remains unclear. Through a targeted RNAi screen in the Drosophila germline, we identify Acetyl-CoA Carboxylase (Acc), the rate-limiting enzyme in fatty acid synthesis (FAS), as an essential regulator of germline stem cell (GSC) maintenance and oocyte development. Acc loss shifts cellular metabolism toward fatty acid oxidation (FAO), fueling the TCA cycle and electron transport chain, which elevates ATP levels and hyperactivates TOR signaling. This metabolic reprogramming induces excessive protein synthesis, disrupting endosomal trafficking and fusome branching, a germline-specific organelle essential for synchronized cell divisions and oocyte selection. These defects are rescued by inhibiting FAO, suppressing TOR activity, reducing protein synthesis, or restricting dietary protein intake. Our study establishes a direct metabolic–signaling–structural axis in the female germline and highlights Acc as a key metabolic checkpoint that safeguards energy balance, intracellular trafficking, and oocyte fate.

Date: 2025
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DOI: 10.1038/s41467-025-65708-w

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