Dual-modal metabolic analysis reveals hypothermia-reversible uncoupling of oxidative phosphorylation in neonatal brain hypoxia-ischemia

• DOI: 10.7554/elife.100129
• Publication Date: 2024-09-25T21:04:35Z
• Authors: Naidi Sun; Yu-Yo Sun; Rui Cao; Hong-Ru Chen; Yiming Wang; Elizabeth Fugate; Marchelle R Smucker; Yi-Min Kuo; P Ellen Grant; Diana M Lindquist; Chia-Yi Kuan; Song Hu
• Keywords: Hypoxia

Hypoxia-ischemia (HI), which disrupts the oxygen supply-demand balance in brain by impairing blood supply and cerebral metabolic rate of (CMRO 2 ), is a leading cause neonatal injury. However, it unclear how post-HI hypothermia helps to restore balance, as cooling reduces CMRO . Also, transient HI leads secondary energy failure (SEF) brains remains elusive. Using photoacoustic microscopy, we examined effects on awake 10-day-old mice, supplemented bioenergetic analysis purified cortical mitochondria. Our results show that while suppresses ipsilateral , sparks prolonged -surge post-HI, associated with increased mitochondrial consumption, superoxide emission, reduced membrane potential necessary for ATP synthesis—indicating oxidative phosphorylation (OXPHOS) uncoupling. Post-HI prevents constraining extraction fraction, stress, maintains N-acetylaspartate levels, resulting attenuated infarction at 24 hours post-HI. findings suggest OXPHOS-uncoupling induced underlies SEF blocking surge key mechanism protection. our study highlights optical -measurements detecting injury guiding titration therapeutic bedside.