Herranz, G.; Alonso-Larre, D.; Gonzalez, T.; Akintche, L.; Ramos-Manzano, A.; Iborra-Pernichi, M.; Velasco de la Esperanza, M.; Diaz-Diaz, C.; Ganley, I.; Boya, P.; Cogliati, S.; Martinez-Martin, N.; Martin-Belmonte, F.

The neonatal gastrointestinal tract mediates nutrient absorption and the establishment of immune tolerance to commensal microbiota. In early life, lysosome-rich enterocytes (LREs) in the ileum are necessary for the intracellular digestion of maternal milk proteins. However, the molecular mechanisms sustaining their function remain incompletely characterized. Here, we demonstrate that LRE mitochondrial homeostasis and autophagic capacity are critical for efficient nutrient uptake and maintenance of their specialized identity, as disruption of either process leads to premature differentiation into adult enterocytes with diminished endolysosomal and metabolic activity. Transcriptomic profiling further revealed that neonatal LREs exhibit a distinctive antioxidant signature, which preserves redox balance and safeguards the expression of the transcriptional regulators MAFB and BLIMP1, both central repressors of the neonatal-to-adult metabolic transition. These findings establish the mitochondria lysosome axis as a key determinant of LRE function and neonatal metabolic programming. They also provide a mechanistic framework for understanding how organelle dysfunction and redox imbalance may contribute to early-life malnutrition syndromes, such as Kwashiorkor, and suggest therapeutic strategies aimed at preserving mitochondrial and lysosomal integrity.