Fig. 8: TNIP1^Q333P mitophagosome recruitment of TNIP1 and mitochondria.

a,b, Immunofluorescence staining of HEK 293 cells overexpressing TNIP1^WT or TNIP1^Q333P (green) stained with Mitotracker Deep Red without treatment (a) or treated with 10 μM oligomycin A for 2 h (b) (red). Cells treated with oligomycin A for 2 h are labeled. Scale bar, 10 μm. Data are representative of n = 2 experiments. c, Representative electron micrographs of submandibular salivary gland ultrathin sections from n = 1 WT and n = 2 homozygous 16-week-old vikala female mice. The red arrowheads indicate swollen mitochondria and the yellow asterisks disorganized cristae. d, Schematic of the proposed model of the molecular impact of Q333P on TNIP1 function. On TLR ligation, TNIP1^WT is activated and recruited to ATG7-LC3B⁺ autophagosomes where it recruits the Myddosome leading to degradation of some of the components and dampening of the signal. Q333P impairs recruitment to autophagosomes and to MyD88. In addition, mitophagy stimulation activates recruitment of TNIP1^WT and selective autophagy receptors, such as TAX1BP1, to sequester damaged and ubiquitinylated mitochondrial components. The interaction probably occurs via the ADH3 domain of TNIP1. Q333P impairs mitophagosome recruitment of TNIP1 and may impact clearance of damaged mitochondria, leading to cytosolic release of mitochondrial damage-associated molecular patterns, mitochondrial RNA or DNA, and activation of the innate TLR7 or TLR9 receptors. The schematic was created with BioRender.com. mtRNA, mitochondrial RNA.

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