Mitochondrial quality control in acute ischemic stroke

Abstract

Mitochondria play a central role in the pathophysiological processes of acute ischemic stroke. Disruption of the cerebral blood flow during acute ischemic stroke interrupts oxygen and glucose delivery, leading to the dysfunction of mitochondrial oxidative phosphorylation and cellular bioenergetic stress. Cells can respond to such stress by activating mitochondrial quality control mechanisms, including the mitochondrial unfolded protein response, mitochondrial fission and fusion, mitophagy, mitochondrial biogenesis, and intercellular mitochondrial transfer. Collectively, these adaptive response strategies contribute to retaining the integrity and function of the mitochondrial network, thereby helping to recover the homeostasis of the neurovascular unit. In this review, we focus on mitochondrial quality control mechanisms occurring in acute ischemic stroke. A better understanding of how these regulatory pathways work in maintaining mitochondrial homeostasis will provide a rationale for developing innovative neuroprotectants when these mechanisms fail in acute ischemic stroke.

Keywords: Acute ischemic stroke; intercellular mitochondrial transfer; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control; mitochondrial unfolded protein response; mitophagy.

Figure 1.

Mitochondrial quality control and intercellular mitochondrial transfer. When exposed to stressors, mitochondria can initiate a set of quality control mechanisms, including the mitochondrial unfolded protein response (UPR^mt), mitochondrial fission and fusion, mitophagy, and mitochondrial biogenesis. In addition, mitochondria can be transferred from adjacent astrocytes to injured neurons as a compensatory internal adaptive response, which is a novel type of mitochondrial quality control mechanism.

Figure 2.

Mechanisms of the mitochondrial unfolded protein response (UPR^mt) in Caenorhabditis elegans and mammalian cells. The UPR^mt is an adaptive transcriptional response that can be activated by various mitochondrial stressors. In C. elegans, the key regulator of UPR^mt is the activation transcription factor associated with stress 1 (ATFS-1), which is continuously transported into mitochondria via mitochondrial targeting sequence (MTS) guidance and cleaved by the Lon protease under physiological conditions. However, the ATFS-1 mitochondria targeting can be suppressed by the accumulation of aberrant peptides in the cytosol, which are unfolded or misfolded proteins that are cleaved by the caseinolytic protease P (CLPP) and extruded into the cytosol via the transporter HAF-1 under stress conditions. Stabilized ATFS-1 translocates through guidance of the nuclear localization sequence (NLS) into the nucleus from where it promotes gene transcription related to mitochondrial chaperones and proteases, detoxification of reactive oxygen species (ROS), innate immunity, and glycolysis. Together, these protective responses facilitate the recovery of mitochondrial homeostasis. UPR^mt in mammalian cells may be regulated by basic leucine zipper (bZip) protein homologs including the C/EBP homologous protein (CHOP), activating transcription factor 4 (ATF4), and activating transcription factor 5 (ATF5), which are transcribed under the control of the integrated stress response (ISR) mechanism mediated by phosphorylated eukaryotic initiation factor-2 alpha subunit (eIF2α). The mitochondrial metallopeptidase OMA1 cleaves the DELE1 protein into short peptides, contributing to heme-regulated inhibitor (HRI) activation, eIF2α phosphorylation, and a general inhibition of gene transcription, while promoting transcription of genes encoding bZip proteins.

Figure 3.

Mechanisms of mitochondrial dynamics and mitophagy under basal conditions and hypoxic/ischemic stress. Typically, fission and fusion machineries balance injured or aged mitochondria by dislodging damaged contents via dynamin-related protein (Drp)1- and dynamin (Dyn)2-mediated fission or merging with other healthy mitochondria via mitofusin (Mfn)1-, Mfn2-, or optic atrophy (Opa)1-mediated fusion. Mitochondria that fail to recover homeostasis will undergo mitophagy in a Parkin-dependent or Parkin-independent (FUNDC1 or NIX/Bnip3L) manner. However, the balance in mitochondrial dynamics shifts to fission under conditions of hypoxic/ischemic stress. Combined with an attenuated mitophagy capacity, these mechanisms collectively lead to the excessive accumulation of damaged mitochondria and irreversible cellular injury.