A Non-Mitophagy Activity of BNIP3L/NIX in Amygdala Glutamatergic Neurons is Essential for Contextual Fear Memory Formation.

Mitochondrial quality is crucial for maintaining brain homeostasis. BNIP3L/NIX, a mitophagy receptor, has been linked to neurological disorders, yet its specific function in the brain remains unclear. We found BNIP3L highly expressed in basolateral amygdala (BLA) neurons. Selective deletion of bnip3l in BLA glutamatergic neurons (BLA(GLU)) impaired contextual fear memory, accompanied by reduced neuronal excitation and mitochondrial respiration. Notably, fear conditioning did not invariably activate mitophagy in BLA(GLU) neurons. Overexpression of both wild-type and a mitophagy-deficient mutant (BNIP3L(ΔLIR)) in BLA(GLU) neurons was sufficient to rescue the contextual fear memory deficits in bnip3l(-/-) mice, suggesting a non-mitophagy role. Instead, we detected a prompt mitochondrial fission in BLA(GLU) neurons after foot-shock conditioning, an effect abolished by bnip3l deletion. Inhibition of Drp1 with Mdivi-1 disrupted memory formation, whereas optogenetic activation of Drp1 restored neuronal excitation and rescued memory deficits in bnip3l(-/-) mice. These data indicated an essential role of BNIP3L-mediated mitochondrial fission in modulating contextual fear memory. Mechanistically, BNIP3L and Drp1 competitively interact with AMPK, leading to reduced Drp1 phosphorylation and increased Drp1 accumulation on mitochondria, thereby promoting mitochondrial fission. Taken together, the present study revealed a previously uncharacterized, non-mitophagy-dependent role for BNIP3L in contextual fear memory conditioning.