Mitochondria: the missing link between preconditioning and neuroprotection

Abstract

The quote "what does not kill you makes you stronger" perfectly describes the preconditioning phenomenon - a paradigm that affords robust brain tolerance in the face of neurodegenerative insults. Over the last few decades, many attempts have been made to identify the molecular mechanisms involved in preconditioning-induced protective responses, and recent data suggests that many of these mechanisms converge on the mitochondria, positing mitochondria as master regulators of preconditioning-triggered endogenous neuroprotection. In this review, we critically discuss evidence for the involvement of mitochondria within the preconditioning paradigm. We will highlight the crucial targets and mediators by which mitochondria are integrated into neuroprotective signaling pathways that underlie preconditioning, putting focus on mitochondrial respiratory chain and mitochondrial reactive oxygen species, mitochondrial ATP-sensitive potassium channels, mitochondrial permeability transition pore, uncoupling proteins, and mitochondrial antioxidant enzyme manganese superoxide dismutase. We also discuss the role of mitochondria in the induction of hypoxia-inducible factor-1, a transcription factor engaged in preconditioning-mediated neuroprotective effects. The identification of intrinsic mitochondrial mechanisms involved in preconditioning will provide new insights which can be translated into potential pharmacological interventions aimed at counteracting neurodegeneration.

Fig. 1

Schematic illustration of the involvement of mitochondrial reactive oxygen species (ROS) in hypoxia-inducible factor 1 (HIF-1) stabilization. HIF-1 is a heterodimeric protein composed of a constitutively expressed HIF-1β subunit and an inducible HIF-1α subunit. In the presence of molecular oxygen (O₂), HIF-1α is hydroxylated by prolyl hydroxylase enzymes (PHDs) and rapidly degraded by ubiquitin-proteasome system. Under hypoxic conditions, the generation of ROS by the mitochondrial respiratory chain inhibits PHDs activity, preventing the hydroxylation of HIF-1α, resulting in HIF-1α stabilization and translocation to the nucleus. Consequently, HIF-1α dimerizes with HIF-1β, initiating the transcription of HIF-1-responsiveness genes.