Crosstalk among mitophagy, pyroptosis, ferroptosis, and necroptosis in central nervous system injuries

Abstract

Central nervous system injuries have a high rate of resulting in disability and mortality; however, at present, effective treatments are lacking. Programmed cell death, which is a genetically determined form of active and ordered cell death with many types, has recently attracted increasing attention due to its functions in determining the fate of cell survival. A growing number of studies have suggested that programmed cell death is involved in central nervous system injuries and plays an important role in the progression of brain damage. In this review, we provide an overview of the role of programmed cell death in central nervous system injuries, including the pathways involved in mitophagy, pyroptosis, ferroptosis, and necroptosis, and the underlying mechanisms by which mitophagy regulates pyroptosis, ferroptosis, and necroptosis. We also discuss the new direction of therapeutic strategies targeting mitophagy for the treatment of central nervous system injuries, with the aim to determine the connection between programmed cell death and central nervous system injuries and to identify new therapies to modulate programmed cell death following central nervous system injury. In conclusion, based on these properties and effects, interventions targeting programmed cell death could be developed as potential therapeutic agents for central nervous system injury patients.

Figure 1

Overview of the mitophagy pathway. Unc-51 like autophagy activating kinase 1 (ULK1) initiates formation of the phagophore by responding to nutrient stress signals from mammalian target of rapamycin (mTOR). Phosphatase and tensin homolog induced kinase 1 (PINK1)-mediated mitophagy. Dynamin-related protein 1 (Drp1) induces the fission of damaged mitochondria (in green) from healthy mitochondria (in blue). The phosphorylated PINK1 accumulates on the outer mitochondrial membrane (OMM) when mitochondria are damaged due to loss of the mitochondrial membrane potential or stimulation by reactive oxygen species (ROS), and subsequently recruits Parkinson protein 2 E3 ubiquitin-protein ligase (Parkin) to the mitochondria. The E3 ligase PRKN polyubiquitinates multiple OMM proteins, which will be recognized by microtubule-associated protein light chain 3 (LC3) receptors, including calcium binding and coiled-coil domain 2 (CALCOCO2), optineurin (OPTN), and p62, on the phagophore. Receptor-mediated mitophagy. Receptors locating at the OMM, including NIP3-like protein X (NIX), BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), and FUN14 domain containing 1 (FUNDC1), bind with LC3 proteins to mediate autophagosome formation. Ubiquitin ligases of mitochondrial E3 ubiquitin ligase 1 (MUL1) and Mitsugumin 53 (MG53) recruit more phagophores to assist in mitophagy implementation. Dephosphorylation of FUNDC1 enhances mitochondrial fission by disassembly of optic atrophy 1 (OPA1) and interaction with dynamin-like protein 1 (DNML1) on the mitochondria. Damaged mitochondria are engulfed by phagophores to form the autophagosome, followed by the fusion with lysosomes to form autolysosomes that degrade the damaged mitochondria. Created with Adobe Photoshop CS4.

Figure 2

Overview of the pyroptosis pathway. In respond to damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), NLR family pyrin domain containing 3 (NLRP3) can recruit and activate caspase-1 via apoptosis-associated speck-like protein containing CARD (ASC) to form the inflammasome. Caspase 4/5/11 are activated in the cytoplasm after stimulated by lipopolysaccharide (LPS). Activated caspase 1/4/5/11 further promotes the cleavage and production of N-terminal domains of gasdermin D (GSDMD-N), leading to pyroptosis. Pyroptosis regulated by potassium efflux triggers the release of high mobility group box 1 (HMGB1) and K⁺. Created with Adobe Photoshop CS4.

Figure 3

Overview of the ferroptosis pathway. The transferrin (TF)-transferrin receptor (TFRC) complex promotes iron accumulation by upregulation of iron uptake and downregulation of iron storage, leading to increased lipid peroxidation (LPO) and ferroptosis. Antioxidant systems, such as system Xc-/glutathione/glutathione peroxidase 4 (system Xc-/GSH/GPX4), can inhibit LPO. Cysteine can be transported into the cell, whereas glutamate (Glu) can be transported out of the cell by the system Xc-. Cysteine can be used to synthesize GSH to maintain the balance of the redox state. Glu can be converted to α-ketoglutarate (α-KG) and participates in tricarboxylic acid (TCA), thereby activating LPO. Polyunsaturated fatty acids (PUFAs) derived from lipids can be catalyzed by acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) to phospholipid-polyunsaturated fatty acids (PL-PUFAs), and PL-PUFAs play a critical role in ferroptosis by promoting LPO. Created with Adobe Photoshop CS4.

Figure 4

Overview of the necroptosis pathway. Following tumor necrosis factor-α (TNF-α) binding to TNF receptor 1 (TNFR1), cellular inhibitor of apoptosis protein (cIAP), TNFR1-associated death domain protein (TRADD), tumor necrosis factor receptor-associated factor (TRAF), and receptor interacting Ser/Thr protein kinase 1 (RIP1) are recruited to form Complex I. cIAP can induce the Lys63-linked polyubiquitination (Lys63-Ub) of RIP1 to increase cell survival. Furthermore, inhibition of cIAP or deubiquitination of RIP1 by cylindromatosis (CYLD) promotes the conversion of Complex I to Complex II. When caspase-8 is activated in Complex II, apoptosis is initiated. When caspase-8 is inhibited or receptor interacting Ser/Thr protein kinase 3 (RIP3) is activated, RIP1, RIP3, and mixed lineage kinase domain-like pseudokinase (MLKL) are recruited to form the necrosome via phosphorylation. Activation of MLKL mediates membrane pore formation and results in necroptosis. Created with Adobe Photoshop CS4.

Figure 5

Crosstalk among mitophagy, pyroptosis, ferroptosis, and necroptosis in central nervous system (CNS) injuries. CNS injuries cause damage to the mitochondrion and activate mitophagy. Mitophagy further attenuates necroptosis, pyroptosis, and ferroptosis, resulting in decreased brain damage. Created with Adobe Photoshop CS4.

Figure 6

Upstream molecules of mitophagy-mediated pyroptosis and necroptosis in central nervous system (CNS) injuries. Following CNS injury, regulation of sirtuin 3 (SIRT3), forkhead box transcription factor 3a (FOXO3a), phosphoglycerate mutase family member 5 (PGAM5), and adenosine monophosphate-activated protein kinase (AMPK) led to the activation of mitophagy through BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), phosphatase and tensin homolog induced kinase 1 (PINK1), and NIP3-like protein X (NIX). Mitophagy subsequently inhibits inflammation, suppresses pyroptosis, decreases necroptosis, and attenuates cell death post-CNS injury. Created with Adobe Photoshop CS4.