Hypothesis

Chronic exposure to gut‑microbiota‑produced succinate drives a maladaptive shift in neuronal autophagy from bulk cytoplasmic recycling to selective mitophagy. This rewiring of the autophagic triage system depletes essential mitochondria, lowering ATP output and rendering neurons vulnerable to stress‑induced death, thereby accelerating neurodegenerative pathology.

Mechanistic Basis

Succinate activates the succinate receptor SUCNR1 (GPR91) on neurons and microglia, stabilizing HIF‑1α even under normoxic conditions. HIF‑1α transcriptionally upregulates BNIP3 and NIX, mitophagy receptors that compete with p62/SQSTM1 for LC3 binding. Under sustained succinate signaling, the Ulk1 complex remains dephosphorylated, favoring AMPK association and biasing autophagosome formation toward mitochondria marked by BNIP3/NIX. Consequently, the cell expends its limited autophagic capacity on organelles that are not expendable, converting a survival‑oriented rationing response into a self‑limiting cannibalism of vital bioenergetic machinery.

This model extends the siege‑rationing view by showing that a specific microbiota metabolite can re‑program the triage logic, turning autophagy from a nutrient‑salvage pathway into a maladaptive selective removal system.

Testable Predictions

1. Neurons exposed to physiological concentrations of succinate will show increased BNIP3‑dependent mitophagy without a proportional increase in bulk protein degradation, measurable by mt‑Keima and DQ‑BSA assays.
2. Genetic or pharmacological inhibition of SUCNR1 in neurons will rescue mitochondrial mass and ATP levels in succinate‑treated cultures, even when autophagy is globally induced by rapamycin.
3. In APP/PS1 mice, chronic administration of a SUCNR1 antagonist will reduce BNIP3‑positive mitophagy markers in hippocampus, preserve synaptic protein levels, and improve performance in the Morris water maze compared with vehicle‑treated controls.
4. Fecal microbiota transplantation from succinate‑high donors into germ‑free mice will exacerbate neurodegeneration markers, an effect abolished by concomitant SUCNR1 blockade.

Experimental Design

In vitro: Primary cortical neurons from WT mice treated with 0.5‑5 mM sodium succinate for 24 h. Conditions include (a) vehicle, (b) succinate + rapamycin, (c) succinate + SUCNR1 inhibitor (NF‑56E J40), (d) succinate + BNIP3 siRNA. Readouts: mitochondrial mass (MitoTracker Green), ATP luminescence, LC3‑II turnover with bafilomycin A1, mitophagy flux (mt‑Keima), and bulk autophagy (DQ‑BSA fluorescence).

In vivo: APP/PS1 mice receive oral SUCNR1 antagonist (10 mg/kg/day) or vehicle from 3 to 6 months of age. Subsets receive FECM from human donors with high fecal succinate. Endpoints: hippocampal BNIP3/p62 immunoreactivity, respirometry of isolated synapses, cognitive testing, and survival.

Falsification would occur if succinate fails to shift autophagy selectivity toward mitochondria, if SUCNR1 blockade does not restore mitochondrial function despite altered autophagy markers, or if neurodegeneration phenotypes are unchanged by manipulating the succinate‑SUCNR1‑BNIP3 axis.