Mitochondrial dysfunction in neonatal brain injury: from molecular mechanisms to therapeutic interventions

Neonatal brain injury, including hypoxic-ischemic encephalopathy, preterm brain injury, and neonatal infectious brain injury, remains a major cause of death and long-term neurodevelopmental disability worldwide. The immature brain is highly dependent on oxidative metabolism yet particularly vulnerable to energy failure and oxidative stress, placing mitochondria at the core of injury cascades. By integrating disturbances in energy production, redox balance, calcium homeostasis, and cell death signaling, mitochondrial dysfunction is increasingly recognized as a unifying driver of diverse neonatal brain injury phenotypes.

This narrative review synthesizes current knowledge on the main clinical forms of neonatal brain injury and their developmental context, alongside an overview of mitochondrial physiology in neural cells, including the regulation of bioenergetics, reactive oxygen species, calcium signaling, mitochondrial dynamics, and inter‑organelle communication. It critically examines how mitochondrial dysfunction contributes to injury across hypoxic-ischemic, preterm, and infectious or inflammatory insults, emphasizing links between impaired oxidative phosphorylation, excessive oxidative and nitrosative stress, calcium overload with pathological opening of the mitochondrial permeability transition pore, activation of apoptosis and regulated necrosis, disrupted mitochondrial fusion-fission balance and biogenesis, and defective mitophagy and mitochondrial quality control. These mitochondrial disturbances precipitate acute neuronal and oligodendroglial injury and hinder the long-term maturation and connectivity of neural circuits. Finally, we review emerging mitochondria‑targeted neuroprotective strategies, focusing on approaches that enhance mitochondrial biogenesis, reduce mitochondrial oxidative stress, and target mitochondrial dynamics to restore mitochondrial homeostasis and improve cellular resilience in the immature brain.

By linking specific patterns of mitochondrial dysfunction to distinct forms and stages of neonatal brain injury, this review provides a mechanistic framework for identifying high‑risk infants, refining pathophysiological understanding, and guiding the rational development of mitochondria‑targeted interventions aimed at improving neurological outcomes in vulnerable newborns.