Mitochondria as the memory of preconditioning

Preconditioning is such a paradigm that a stimulus below the threshold of causing harm makes the brain stronger and resilient to subsequent injury. Preconditioning affords a vigorous tolerance to the brain against neurodegeneration. Numerous efforts have tried to identify the molecular targets involved in preconditioning-induced protective responses and interestingly many of those diverse mechanisms posit mitochondria as a master regulator of preconditioning. Therefore, in this review, we will critically discuss recent and emerging evidence for the involvement of mitochondria within the preconditioning paradigm. We will introduce the crucial targets and signaling cascades by which mitochondria exert preconditioning with a focus on white matter mitochondria and whether and how mechanisms for preconditioning differ in neurons and glial cells. In this aspect, we will evaluate the role of mitochondrial shaping proteins to establish structure-function interdependence for fusion-fission balance, motility, ATP production, Ca⁺², and ROS scavenging. We will also discuss how aging impacts mitochondria and the consequences of mitochondrial aging on preconditioning mechanisms. We will concentrate on the regulation of mitochondrial DNA content and quantification specifically for its value as a biomarker to monitor disease conditions. The identification of these mitochondrial preconditioning mechanisms can be translated to potential pharmacological interventions to increase intrinsic resilience of the brain to injury and to develop novel approaches to neurodegenerative diseases. Moreover, mitochondria dynamics can be used as a memory or biomarker of preconditioning.