Mitophagy in acute central nervous system injuries: regulatory mechanisms and therapeutic potentials

Abstract

Acute central nervous system injuries, including ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, and spinal cord injury, are a major global health challenge. Identifying optimal therapies and improving the long-term neurological functions of patients with acute central nervous system injuries are urgent priorities. Mitochondria are susceptible to damage after acute central nervous system injury, and this leads to the release of toxic levels of reactive oxygen species, which induce cell death. Mitophagy, a selective form of autophagy, is crucial in eliminating redundant or damaged mitochondria during these events. Recent evidence has highlighted the significant role of mitophagy in acute central nervous system injuries. In this review, we provide a comprehensive overview of the process, classification, and related mechanisms of mitophagy. We also highlight the recent developments in research into the role of mitophagy in various acute central nervous system injuries and drug therapies that regulate mitophagy. In the final section of this review, we emphasize the potential for treating these disorders by focusing on mitophagy and suggest future research paths in this area.

Figure 1

Mitochondrial quality control. Mitochondrial quality control mechanisms include mitochondrial dynamics, mitophagy, and mitochondrial biogenesis. Mitochondrial dynamics involve two contrasting processes: fusion and fission. Fusion mechanisms facilitate the tethering and merging of two mitochondria, while fission triggers the cleavage and division of mitochondria. Mitochondrial fission is mainly modulated by DRP1, and fusion is mainly modulated by MFN1, MFN2, and OPA1. Mitochondria unable to restore homeostasis undergo mitophagy. Mitobiogenesis is the mechanism by which the quantity and size of mitochondria increase in response to elevated energy requirements or mitochondria removed through mitophagy are replaced. Created with BioRender.com. DRP1: Dynamin-related protein 1; MFN1: mitofusin 1; MFN2: mitofusin 2; OPA1: optic atrophy protein 1.

Figure 2

Mitophagy pathways. Mitophagy pathways are normally divided into the ubiquitin-dependent pathway and receptor-mediated pathway. (A) PINK1 induces the phosphorylation of the E3 ligase Parkin. Active Parkin builds a ubiquitin chain on MOM proteins, and thus recruits autophagy receptors, which link the labeled mitochondria to autophagosomes through their LC3-interacting motifs, resulting in mitophagy. (B) Other E3 ubiquitin ligases, e.g., GP78, SIAH1, and MUL1, have been reported to regulate mitophagy in a manner dependent on ubiquitin but independent of PINK1 and Parkin. (C) Some autophagy receptors, such as BNIP3, NIX, FUNDC1, BCL2L13, FKBP8, and AMBRA1, are anchored in the OMM; their binding to LC3 on the phagophore initiates mitophagy. (D) Other autophagy receptors, such as PHB2 and cardiolipin, are anchored in the IMM, and their binding to LC3 on the phagophore also initiates mitophagy. Created with BioRender.com. AMBRA1: Autophagy/Beclin-1 regulator-1; BCL2L13: Bcl2 like 13; BNIP3: BCL2 19 kDa interacting protein 3; FKBP8: FK506-binding protein 8; FUNDC1: FUN14 domain-containing protein 1; GP78: glycoprotein 78; LC3: microtubule associated protein 1 light chain 3; MUL1: mitochondrial E3 ubiquitin ligase 1; PHB2: prohibitin 2; PINK1: PTEN-induced putative kinase protein 1; SIAH1: seven in absentia homolog 1.

Figure 3

Schematic illustration of roles of mitophagy in acute central nervous system injuries. Created with BioRender.com.

Figure 4

Genes affecting mitophagy in acute central nervous system injuries. (A) Genes affecting mitophagy in ischemic stroke. PA2G4, ATG5, ATG7, or BNIP3 downregulation inhibits mitophagy, thereby contributing to increased reperfusion injury. Downregulation of EIF2S1, ATF4, or PARK2 inhibits PARK2-mediated mitophagy, resulting in exacerbated reperfusion injury. Downregulation of PGC-1α inhibits the expression of ULK1, resulting in decreased mitophagy and exacerbated reperfusion injury. Upregulation of FUNDC1, BNIP3, ATF4, PARK2, USP18, or FTO increases mitophagy levels and protects the brain against I/R injury. Excessive mitophagy is detrimental and inhibiting the overactivation of mitophagy protects the brain against I/R injury. Downregulation of PRDX6 promotes PINK1/Parkin-mediated mitophagy, thereby exacerbating reperfusion injury. Downregulation of ATG5 inhibits mitophagy, thus protecting the brain against I/R injury. (B) Genes affecting mitophagy in intracerebral hemorrhage. PINK1 or FUNDC1 downregulation inhibits mitophagy, thus leading to increased injury after ICH. Upregulation of PINK1, FUNDC1, or mitofilin increases mitophagy levels and protects the brain after ICH. (C) Genes affecting mitophagy in subarachnoid hemorrhage. USP30 downregulation promotes mitophagy and thereby protects the brain after SAH. (D) Genes affecting mitophagy in traumatic brain injury. Upregulation of NIX or PINK1/Parkin increases mitophagy, thereby protecting the brain against traumatic brain injury. Downregulation of cardiolipin inhibits mitophagy, leading to increased injury. (E) Genes affecting mitophagy in spinal cord injury. Upregulation of GIT1 increases mitophagy, protecting the spinal cord against injury. Downregulation of GIT1 decreases mitophagy, resulting in an exacerbation of injury. Created with BioRender.com. ATF4: Activating transcription factor 4; ATG5: autophagy related 5; ATG7: autophagy related 7; EIF2S1: eukaryotic translation initiation factor 2 subunit alpha; FTO: fat mass and obesity-associated protein; GIT1: GPCR kinase 2-interacting protein-1; I/R: ischemia/reperfusion; PA2G4: proliferation-associated protein 2G4; PGC-1α: peroxisome proliferator-activated receptor-γ coactivator1α; PRDX6: peroxiredoxin 6; ULK1: Unc-51 like kinase 1; USP18: ubiquitin-specific peptidase 18; USP30: ubiquitin-specific peptidase 30.

Figure 5

Timeline of research progress in the role of mitophagy in acute central nervous system injuries. Created with BioRender.com.