# Immune regulators PALS-25 and PALS-22 localize to mitochondria and regulate mitochondrial fragmentation in C. elegans **Authors:** Spencer S. Gang, Max W. Strul, Desmond Richmond-Buccola, Emily R. Troemel PMC · DOI: 10.1016/j.isci.2026.114814 · iScience · 2026-01-27 ## TL;DR This study shows that PALS-22 and PALS-25 proteins in C. elegans localize to mitochondria and regulate mitochondrial fragmentation to enhance immunity against intracellular pathogens. ## Contribution The study reveals the mitochondrial localization and mechanism of action of PALS-22 and PALS-25 in regulating immunity. ## Key findings - PALS-22 and PALS-25 proteins localize to mitochondria in C. elegans. - The C-terminus of PALS-25 is responsible for mitochondrial localization. - Loss of PALS-22 causes mitochondrial fragmentation and increases resistance to microsporidia. ## Abstract The nematode C. elegans controls immunity against intracellular pathogens such as microsporidia, using the pals gene family, which has expanded in C. elegans compared to mammals. pals-22 is a negative regulator that restrains pals-25, which serves as a positive regulator of immunity. pals-22 and pals-25 encode proteins that bind each other and can act in the intestine and epidermis, but their subcellular localization and mechanism of action have not been described. Here, we show that PALS-22 and PALS-25 proteins localize to mitochondria, with PALS-25 being required for PALS-22 localization to mitochondria. The C-terminus of PALS-25 directs mitochondrial localization, and the N-terminus is required for signaling. The loss of PALS-22 causes mitochondrial fragmentation, which occurs after activating the intracellular pathogen response (IPR), a transcriptional program induced by intracellular infection. Mitochondrial fragmentation induced by knockdown of fission/fusion factors increases resistance against microsporidia infection. Thus, the PALS-22/25-mediated fragmentation of mitochondria enhances resistance against intracellular infection. •PALS-22 and PALS-25 localize to the outer membrane of mitochondria•PALS-25 C-terminal half directs mitochondrial localization•Loss of PALS-22 triggers mitochondrial fragmentation through IPR induction PALS-22 and PALS-25 localize to the outer membrane of mitochondria PALS-25 C-terminal half directs mitochondrial localization Loss of PALS-22 triggers mitochondrial fragmentation through IPR induction Cellular physiology; Immunity; Cell biology ## Linked entities - **Genes:** pals-22 (Retrotrans_gag domain-containing protein) [NCBI Gene 175180], pals-25 (Protein containing ALS2cr12 (ALS2CR12) signature) [NCBI Gene 188564] - **Proteins:** pals-22 (Retrotrans_gag domain-containing protein), pals-25 (Protein containing ALS2cr12 (ALS2CR12) signature) ## Full-text entities - **Genes:** unc-54 (Myosin-4) [NCBI Gene 259839], lig-4 (DNA ligase IV) [NCBI Gene 176067], eat-3 (Dynamin-like GTPase OPA1, mitochondrial) [NCBI Gene 174476], SLC39A1 (solute carrier family 39 member 1) [NCBI Gene 27173] {aka ZIP1, ZIRTL}, drh-1 (Helicase ATP-binding domain-containing protein;RNA helicase) [NCBI Gene 177425], hsp-60 (Chaperonin homolog Hsp-60, mitochondrial;Heat shock protein 60) [NCBI Gene 175316], zip-2 (Transcription factor zip-2) [NCBI Gene 175240], zip-1 (BZIP domain-containing protein) [NCBI Gene 176656], fzo-1 (Transmembrane GTPase fzo-1) [NCBI Gene 173990], CRMP1 (collapsin response mediator protein 1) [NCBI Gene 1400] {aka CRMP-1, DPYSL1, DRP-1, DRP1, ULIP-3}, drp-1 (Dynamin-1-like protein drp-1) [NCBI Gene 177336], tir-1 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase;NAD(+) hydrolase tir-1;Sterile alpha and TIR motif-containing protein 1) [NCBI Gene 175502], hlh-30 (Helix-loop-helix protein 30) [NCBI Gene 177157], snb-1 (Synaptobrevin-1) [NCBI Gene 266648], pink-1 (Serine/threonine-protein kinase pink-1, mitochondrial) [NCBI Gene 173918], atfs-1 (Stress activated transcription factor atfs-1) [NCBI Gene 179922], hsf-1 (Heat shock transcription factor hsf-1) [NCBI Gene 173078], unc-119 (Protein unc-119) [NCBI Gene 176519], hsp-6 (Heat shock protein hsp-6) [NCBI Gene 178873] - **Diseases:** N. parisii infection (MESH:D007239), microsporidia infection (MESH:D016881), Mitochondrial fragmentation (MESH:D012892) - **Chemicals:** agar (MESH:D000362), acetone (MESH:D000096), fatty acid (MESH:D005227), polyacrylamide (MESH:C016679), streptomycin (MESH:D013307), sodium hypochlorite (MESH:D012973), fat (MESH:D005223), NGM (-), Tween 20 (MESH:D011136), carbenicillin (MESH:D002228), DTT (MESH:D004229), PBS (MESH:D007854), SDS (MESH:D012967), PVDF (MESH:C024865), DMSO (MESH:D004121), levamisole (MESH:D007978), ethanol (MESH:D000431), NaOH (MESH:D012972), Auxin (MESH:D007210), ATP (MESH:D000255), IPTG (MESH:D007544), agarose (MESH:D012685) - **Species:** Microsporidia (microsporidians, phylum) [taxon 6029], Pseudomonas aeruginosa (species) [taxon 287], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], Escherichia coli (E. coli, species) [taxon 562], Nematocida parisii (species) [taxon 586133], C. elegans [taxon 328850], Orsay virus (species) [taxon 977912] - **Cell lines:** PALS-22 — Homo sapiens (Human), Human papillomavirus-related endocervical adenocarcinoma, Cancer cell line (CVCL_B1ZV), -25 — Homo sapiens (Human), Gastric tubular adenocarcinoma, Cancer cell line (CVCL_W522), OP50-1 — Homo sapiens (Human), q11.2) BCR-ABL1, Cancer cell line (CVCL_DG77) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12937023/full.md ## Figures 8 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12937023/full.md ## References 56 references — full list in the complete paper: https://tomesphere.com/paper/PMC12937023/full.md --- Source: https://tomesphere.com/paper/PMC12937023