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Cited by 11Lipid metabolism and biosynthesisMitochondrial Function and PathologyMetabolism, Diabetes, and Cancer

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Mitochondrial control of glycerolipid synthesis by a PEP shuttle

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Yamamuro, Tadashi, Katoh, Daisuke, Silva, Guilherme Martins, Nishida, Hiroshi, Oikawa, Satoshi, Higuchi, Yusuke, Wang, Dandan, Fujimoto, Masanori, Yoshida, Naofumi, Li, Mark, Shin, Jihoon, Zhao, Zezhou, Yook, Jin-Seon, Sun, Lijun, Kajimura, Shingo·2026·Cell
DOI 10.1016/j.cell.2026.02.017PMC PMC12724411

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Abstract

Mitochondria provide a variety of metabolites, in addition to ATP, to meet cell-specific needs. One such metabolite is phosphoenolpyruvate (PEP), which contains a higher-energy phosphate bond than ATP and has diverse biological functions. However, how mitochondria-generated PEP is delivered to the cytosol and fulfills cell-specific requirements remains elusive. Here, we show that SLC25A35 regulates mitochondrial PEP efflux and glyceroneogenesis in lipogenic cells that utilize the pyruvate-to-PEP bypass. Reconstitution and structural studies demonstrated PEP transport by SLC25A35 in a pH gradient-dependent manner. Loss of SLC25A35 in adipocytes impaired the conversion of mitochondrial PEP into glycerol-3-phosphate, thereby reducing glycerolipid synthesis. Significantly, hepatic inhibition of SLC25A35 in obese mice alleviated steatosis and improved systemic glucose homeostasis. Together, these results suggest that mitochondria facilitate glycerolipid synthesis by providing PEP via SLC25A35, offering lipogenic mitochondria as a target to limit glycerolipid synthesis, a pivotal step in the pathogenesis of hepatic steatosis and type 2 diabetes.

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Metadata

Authors
Yamamuro, T., Katoh, D., Silva, G. M., Nishida, H., Oikawa, S., Higuchi, Y., Wang, D., Fujimoto, M., Yoshida, N., Li, M., Shin, J., Zhao, Z., Yook, J.-S., Sun, L., & Kajimura, S.
Affiliations
Beth Israel Deaconess Medical Center (US)
Corresponding author
Kajimura, Shingo
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2026-05
Volume
189
Issue
10
Pages
2988-3003.e23
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2026.02.017
PMC
PMC12724411
OpenAlex
W7138460936
Cited by
11
References
7
Citations by year
2026: 11
FWCI
25.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed Central (submittedVersion)
Funders
  • American Heart Association Inc
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • The Uehara Memorial Foundation
  • Manpei Suzuki International Prize for Diabetes Research
  • Nakatomi Foundation
  • Howard Hughes Medical Institute
  • Japan Society for the Promotion of Science
  • Kowa Life Science Foundation
  • Takeda Science Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
phosphoenolpyruvate, glycerolipid biosynthesis, glyceroneogenesis, mitochondrial membrane transport, adipocytes, hepatic steatosis, glucose homeostasis, type 2 diabetes, mitochondrial metabolism

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