Tert-Butylhydroquinone Reversed Age-Dependent Hypothalamic Mitochondrial Dysfunction Linking Maternal Fructose Exposure to Synaptic Vulnerability.

Maternal nutrition shapes offspring brain metabolism and later-life vulnerability. Excessive fructose intake during pregnancy and lactation has been linked to hypothalamic metabolic dysregulation, yet the mitochondrial basis of this programming remains unclear. We examined female Sprague-Dawley offspring from dams fed a normal diet (ND) or high-fructose diet (HFD) during gestation and lactation at 1 and 3 months of age. Maternal HFD produced age-dependent suppression of hypothalamic electron transport chain activity, accompanied by increased oxidative protein modification, together with a shift toward mitochondrial fission/fragmentation and limited induction of fusion markers. By 3 months, PGC-1α/TFAM upregulation emerged alongside a pronounced reduction of synaptic proteins, including synaptophysin, PSD95, and Tau, suggesting that cumulative mitochondrial and redox stress is associated with molecular synaptic vulnerability. In the paraventricular nucleus, Nrf2 immunoreactivity in NeuN-positive neurons showed a perinuclear punctate pattern that was diminished by maternal HFD and restored by intervention. Notably, a 2-week course of the electrophilic antioxidant tert-butylhydroquinone (tBHQ) prior to 3-month analysis reduced oxidative damage, enhanced Nrf2-associated antioxidant signaling, and normalized synaptic protein expression. Together, these findings identify an age-gated hypothalamic mitochondrial-redox phenotype linking maternal fructose exposure to molecular synaptic vulnerability in female offspring and highlight the Nrf2-associated redox signaling as a candidate modifiable pathway in maternal diet-induced neuro-metabolic programming.