Sodium ferrous citrate in 5-Aminolevulinic acid supplements suppresses the effector function of feline lymphocytes by reducing the mitochondrial membrane potential

  • Res Vet Sci. 2025 May:187:105603. doi: 10.1016/j.rvsc.2025.105603.
Shoma Nishibori  1 ,  Aika Chijiwa  1 ,  Satoshi Kambayashi  2 ,  Nao Iwatani  3 ,  Aki Sakai  3 ,  Keishiro Isayama  4 ,  Yoichi Mizukami  4 ,  Nobuyuki Shiranaga  5 ,  Takuya Mizuno  6 ,  Masaya Igase  7
Affiliations
  • 1. Laboratory of Molecular Diagnostics and Therapeutics, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan.
  • 2. Laboratory of Veterinary Internal Medicine, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan.
  • 3. One Health Business Department, Neopharma Japan Co., Ltd., Tokyo, Japan.
  • 4. Institute of Gene Research, Science Research Center, Yamaguchi University, Yamaguchi, Japan.
  • 5. Shiranaga Animal Hospital, Yamaguchi, Japan.
  • 6. Laboratory of Molecular Diagnostics and Therapeutics, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan; Research Institute for Cell Design Medical Science, Yamaguchi University, Yamaguchi, Japan.
  • 7. Laboratory of Molecular Diagnostics and Therapeutics, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan; Research Institute for Cell Design Medical Science, Yamaguchi University, Yamaguchi, Japan. Electronic address: [email protected].
PMID: 40048774 DOI: 10.1016/j.rvsc.2025.105603
Abstract

5-Aminolevulinic acid (5-ALA) is an endogenous amino acid in mammalian cells; it is the first amino acid in the heme biosynthesis pathway occurring in the mitochondria. 5-ALA with sodium ferrous citrate (SFC) possesses anti-inflammatory properties by inducing heme oxygenase (HO)-1 expression and releasing heme metabolites in humans and mice. Supplements containing 5-ALA and divalent iron is available in veterinary medicine. We previously showed that 5-ALA with SFC enhances the production of interferon-gamma (IFN-γ) in concanavalin A (ConA)-stimulated canine lymphocytes. However, the effects of 5-ALA/SFC on feline lymphocytes remain to be investigated. This study demonstrated that 5-ALA/SFC-induced HO-1 expression and decreased IFN-γ production in ConA-stimulated feline lymphocytes. Comprehensive RNA Sequencing analysis revealed that the activating transcription factor 4 (ATF4) signaling pathway was inhibited by adding 5-ALA/SFC. Moreover, we confirmed that 5-ALA/SFC decreased ATF4 protein expression. Furthermore, separate analyses of the effects of 5-ALA and SFC on feline lymphocytes revealed that SFC, but not 5-ALA, induced Akt dephosphorylation and mitochondrial dysfunction in activated lymphocytes. Thus, SFC in 5-ALA supplements may suppress the effector function of feline lymphocytes via Mitochondrial Metabolism, thereby representing a novel mechanism in 5-ALA/SFC research.

Keywords
5-Aminolevulininc acid; ATF4; Feline; Mitochondria; Sodium ferrous citrate.
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