Trafficking of protein kinases to mitochondria: Implications for ischemic stroke

Stroke is a major cause of death and permanent disability, which is described by abrupt loss of neuronal energy, oxidative injury, inflammation, and apoptosis, primarily mediated by mitochondrial dysfunction. Mitochondria are key regulators of stress responses, apoptosis, redox homeostasis, immune signaling and known as central signaling hubs, integrating pathways from multiple cellular compartments to maintain homeostasis. Among the major regulatory elements are protein kinase enzymes that modulate cell signaling by phosphorylating substrates. Several kinases, including members of the Akt, PKA, PKC, GSK-3β, PINK1, and MAPK families, dynamically translocate to mitochondria under physiological and pathological conditions. Once localized, they influence mitochondrial dynamics, bioenergetics, reactive oxygen species (ROS) production, and programmed cell death. Dysregulation of these functions has been implicated in impaired mitophagy, aberrant calcium signaling, and processes associated with the pathogenesis of various neurological disorders, particularly in those with acute brain injuries, such as acute ischemic stroke (AIS). Especially, mitochondrial kinase oxidative stress hallmarks of neuronal injury. In this review, we examine the role of mitochondrial-associated kinases in AIS, explore mechanisms of their translocation, downstream signaling effects, and their promise as druggable targets highlighting the importance of spatial dynamics of kinases and the need for precision therapies. Understanding these mechanisms may open new avenues for therapeutic intervention in neurological diseases with a focus on acute brain injury, by targeting mitochondrial signaling networks.