Linnehan, B. | Search bioRxiv

bioRxiv2026

NDUFA4L2 rescues hyperoxia-induced migration defects in retinal endothelial cells by reversing isocitrate dehydrogenase flux blockade

Retinopathy of prematurity (ROP) is caused by hyperoxic exposure of prematurely born infants. The mouse model of oxygen-induced retinopathy (OIR) recapitulates pathological features of both phase I and phase II ROP. We here looked at the retinal proteins that change in response to hyperoxia in phase I of the mouse model of OIR. Using tandem mass tag labeled proteomics, we found several differentially expressed proteins (DEPs) in phase I of OIR. Of all the DEPs, we investigated the role of previously unknown protein NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2). NDUFA4L2 protein and its paralog NDUFA4 are both mitochondrial complex I proteins; however, here we demonstrate that NDUFA4L2 changes in both phases of OIR, with no changes in its paralog NDUFA4, implying its unique function in pathophysiology of the disease. We demonstrate that NDUFA4L2 is an oxygen-sensitive protein and regulates retinal endothelial cell migration by rescuing isocitrate dehydrogenase flux impaired by hyperoxia in phase I of OIR.

biochemistry↗

bioRxiv2026

A Preoptic Neurocircuit That Modulates Metabolic Flexibility

Precise, dynamic control of metabolic fuel usage in response to environmental challenges such as altered food availability or temperature change is essential for animal survival. In mammals, metabolic flexibility--the capacity to shift cellular metabolism between carbohydrate and fatty acid oxidation--is understood to be largely regulated by circulating hormones such as insulin and glucagon. However, the role of the central nervous system in coordinating fuel selection and tissue metabolic tuning remains underexplored. Here, we investigated the mechanisms that mediate metabolic reprogramming following the acute activation of torpor-associated glutamatergic Adcyap1+ torpor-regulating neurons in the anteroventral preoptic area (avPOAVglut2/PACAP). The activation of these neurons rapidly shifts whole-body fuel use from glucose to fatty acids, irrespective of fuel/food availability. This shift is associated with reduced glucose utilization stemming from the transient induction of selective insulin resistance in skeletal muscle. We find that this reduction in skeletal muscle glucose metabolism does not require direct muscle innervation but is rather mediated in part via corticosterone. In contrast to their activation, avPOAVglut2/PACAP neuronal silencing results in improved glucose tolerance, demonstrating powerful bidirectional control of tissue-specific glucose metabolism, whole-body glucose levels, and fuel usage. Together, our findings uncover a novel POA -skeletal muscle pathway that dynamically controls glucose utilization and metabolic flexibility.

neuroscience↗