Lysosomal reduced thiols are essential for mouse embryonic development

• 成果类型: Article
• 署名作者: Adelmann, Charles H.; Venkatachalam, Avanthika; Huang, Lingjuan; Liu, Michelle; Germana, Sharon; Harry, Stefan A.; Rosen, Paul C.; Herron, Joshua; Tien, Pei- Chieh; Bar-Peled, Liron; Sabatini, David M.; Fisher, David E.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Czech Academy of Sciences; Institute of Organic Chemistry & Biochemistry of the Czech Academy of Sciences
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8686
• DOI: 10.1073/pnas.2427125122
• 发表日期: 2025-09-09
• 关键词: cystathionine gamma-lyase; unfolded protein response; gene; expression; transport; identification; inhibition; catabolism; reduction; induction

摘要

While it has been appreciated for decades that lysosomes can import cysteine, its significance for whole- organism physiology has remained uncertain. Recent work identified MFSD12 as a transmembrane protein required for cysteine import into lysosomes (and melanosomes), enabling genetic interrogation of this pathway. Here, we show that Mfsd12 knockout mice die between embryonic days 10.5 and 12.5, indicating that MFSD12 is essential for organogenesis. Mfsd12 loss results in the expression of genes involved in cellular stress and thiol metabolism and likely disproportionately affects the erythroid, myeloid, and neuronal lineages. Within lysosomes, imported cysteine is largely oxidized to cystine, which is exported to the cytosol by the cystinosin (CTNS) transporter. However, unlike Mfsd12, loss of Ctns is compatible with viability, suggesting that the essential role of MFSD12 lies not in supplying cystine to the cytosol, but in providing reduced cysteine within the lysosomal lumen. Supporting this model, maternal treatment with cysteamine-a lysosome- penetrant thiol-rescued the development of Mfsd12 knockout embryos, yielding viable adult offspring. These findings establish lysosomal thiol import as a critical metabolic pathway and provide genetic tools to further clarify its physiological and biochemical roles.