Mitochondrial dysfunction in intracerebral hemorrhage: molecular mechanisms and pathological consequences

Abstract

Intracerebral hemorrhage (ICH) carries high rates of disability and mortality, with a poor prognosis largely attributable to secondary brain injury (SBI). Mitochondria, a central hub for cellular redox regulation and energy metabolism, are not only affected by SBI but can also, once dysfunctional, initiate and exacerbate SBI. In this review, we classify post-ICH mitochondrial dysfunction into three major categories: excessive accumulation of mitochondrial reactive oxygen species, dysregulation of energy metabolism, and dysregulation of mitochondrial quantity and quality control. We delineate the molecular mechanisms and pathological consequences of each. Furthermore, given the extensive crosstalk between mitochondrial dysfunction and diverse forms of cell death in ICH (e.g., apoptosis, necrosis, necroptosis, ferroptosis, and pyroptosis), we discuss their mechanistic links. Overall, this review proposes a mitochondria-centered framework and emphasizes crosstalk between different types of dysfunction, thereby advancing our understanding of SBI pathophysiology after ICH and providing a systematic perspective on therapeutic strategies aimed at restoring mitochondrial homeostasis.