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Microbial Peptidoglycan Activates Mitophagy via Binding Autophagy Adaptor p62 to Protect Liver Health

ABSTRACT: Mitophagy is essential for preserving mitochondrial integrity and liver homeostasis, yet the specific microbial signals that regulate it are poorly defined. Since the gut microbiota significantly influences liver health, identifying specific bacterial factors capable of directly modulating hepatocyte mitophagy may offer new therapeutic avenues. Here, we identify bacterial peptidoglycan (PGN), a ubiquitous cell wall component, as a potent inducer of hepatocyte mitophagy and a protective agent against liver fibrosis. We demonstrate that PGN alleviates drug-induced hepatocyte death in vitro and attenuates carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice. Mechanistically, PGN is internalized by hepatocytes, localizes to mitochondria, and initiates mitophagy by binding directly to the autophagic adaptor p62 (also known as SQSTM1). The essential role of this pathway was confirmed, as genetic ablation of p62 in hepatocytes completely abolished PGN-induced mitophagy. Therapeutically, PGN administration reduced collagen deposition and suppressed hepatic stellate cell activation by enhancing autophagic flux. Collectively, our work unveils a gut microbiota-mitophagy axis wherein PGN acts as a microbial trigger for mitochondrial quality control, presenting a novel therapeutic strategy for mitigating liver fibrosis and associated mitochondrial dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE347163 | GEO | 2026/09/21

REPOSITORIES: GEO

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Project description:Background & Aims Porphyrias are rare metabolic disorders arising from defects in heme biosynthesis, leading to accumulation of toxic porphyrin intermediates, oxidative stress, mitochondrial dysfunction, and liver injury. Current therapies are limited in efficacy, emphasizing the need for novel treatments. Prior studies showed hepatocyte-specific β-catenin deletion attenuates porphyrin accumulation, protein aggregation, and liver injury in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced porphyria. We hypothesized that inhibiting components of the Wnt-β-catenin-glutamine synthesis (GS) signaling pathway reduces heme synthesis and also enhances porphyrin clearance by activating autophagy and improving mitochondrial quality control. Methods We combined pharmacologic Wnt inhibition and hepatocyte-specific GS deletion in mice fed DDC diet. Readouts included spatial transcriptomics, targeted metabolomics, immunohistochemistry, confocal mt-Keima imaging, high-resolution respirometry, and transmission electron microscopy. Human liver biopsies and explants from porphyria patients were also examined by dual-label immunohistochemistry. Results Wnt inhibition during DDC suppressed upregulation of porphyrin biosynthesis genes, reduced porphyrin intermediate accumulation, and enhanced autophagic flux. GS deletion attenuated porphyrin biosynthesis by limiting intracellular glutamine, while also decreasing mTOR activity. Combined Wnt and GS deletion produced additive increases in autophagy and further reduced porphyrin accumulation. Wnt inhibition restored mitophagy, whereas GS deletion primarily improved mitochondrial coupling efficiency. Patient samples mirrored murine findings, with heme enzymes and β-catenin increased in porphyria cutanea tarda and autophagy inversely correlated with β-catenin expression. Conclusions Disrupting Wnt/GS signaling increases autophagy and reduces porphyrin formation, establishing a link between Wnt-driven metabolic signaling and heme pathway regulation in mouse and human liver. These findings identify the Wnt signaling pathway as a potential therapeutic target in porphyria."

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Microbial Peptidoglycan Activates Mitophagy via Binding Autophagy Adaptor p62 to Protect Liver Health

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