Mitochondrial dysfunction and quality control lie at the heart of subarachnoid hemorrhage

Abstract

The dramatic increase in intracranial pressure after subarachnoid hemorrhage leads to a decrease in cerebral perfusion pressure and a reduction in cerebral blood flow. Mitochondria are directly affected by direct factors such as ischemia, hypoxia, excitotoxicity, and toxicity of free hemoglobin and its degradation products, which trigger mitochondrial dysfunction. Dysfunctional mitochondria release large amounts of reactive oxygen species, inflammatory mediators, and apoptotic proteins that activate apoptotic pathways, further damaging cells. In response to this array of damage, cells have adopted multiple mitochondrial quality control mechanisms through evolution, including mitochondrial protein quality control, mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and intercellular mitochondrial transfer, to maintain mitochondrial homeostasis under pathological conditions. Specific interventions targeting mitochondrial quality control mechanisms have emerged as promising therapeutic strategies for subarachnoid hemorrhage. This review provides an overview of recent research advances in mitochondrial pathophysiological processes after subarachnoid hemorrhage, particularly mitochondrial quality control mechanisms. It also presents potential therapeutic strategies to target mitochondrial quality control in subarachnoid hemorrhage.

Keywords: mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial fission and fusion; mitochondrial quality control; mitophagy; subarachnoid hemorrhage.

Figure 1

Initiation and amplification of mitochondrial dysfunction in SAH. After SAH, mitochondria are directly affected by ischemia and hypoxia, excitotoxicity, and toxicity of hemoglobin and its degradation products, which trigger mitochondrial dysfunction and lead to the collapse of ΔΨm. Subsequently, mitochondrial dysfunction leads to the massive production of mtROS, release of mtDAMP, and activation of the mitochondrial apoptotic pathway. Simultaneous excitotoxicity increases the Ca²⁺ inward flow, triggering calcium-dependent MPT, which further increases ROS production and apoptotic protein release. This process ultimately leads to oxidative stress, inflammation, and apoptosis, amplifying cellular damage. Created using used Adobe Illustrator 2021, with material from Servier Medical Art. AMPA: α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; Apaf1: apoptotic protease-activating factor 1; Bax/Bak: BCL2-associated X/BCL2 antagonist/killer 1; CytC: cytochrome c; Hb: hemoglobin; MPT: mitochondrial permeability transition; mtDAMP: mitochondrial damage-associated molecular patterns; mtROS: mitochondrial reactive oxygen species; NMPA: N-methyl-D-aspartate; ROS: reactive oxygen species; SAH: subarachnoid hemorrhage; ΔΨm: mitochondrial membrane potential.

Figure 2

Mitochondrial quality control in SAH. This schematic represents the quality control mechanisms of mitochondria after SAH, including UPRmt, mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and intercellular mitochondrial transfer. First, at the protein level, the MtQC process called UPRmt involves HSP60 and mtHSP70 entering the mitochondria and restoring the normal conformation of misfolded proteins. Second, at the organelle level, dysfunctional mitochondria can undergo mitochondrial outer and inner membrane fusion via MFN1, MFN2, or OPA1. Mitochondrial fusion prevents the accumulation of damaged contents in individual mitochondria through the exchange of mtDNA, proteins, and metabolites between healthy and damaged mitochondria. Dysfunctional and damaged mitochondria can also be separated by fission. Drp1 translocates from the cytoplasm to the outer mitochondrial membrane and mediates fission through Dyn2 to form two unequal mitochondria. The damaged mitochondria produced by fission are then degraded by mitophagy via the PINK1/Parkin-dependent or PINK1/Parkin-independent pathway. Various stimuli lead to the activation of PGC-1α, which then binds to Nrf1/2 to promote the expression of several mitochondrial proteins, including TFAM, ultimately leading to increased mitochondrial biogenesis. Mitochondria are transported between cells by actin-based TNT or EVs released from healthy neurons (or donor cells) that are then internalized into injured neurons. Mitochondrial transfer rescues cells containing damaged mitochondria by translocating healthy mitochondria from neighboring cells. Created using used Adobe Illustrator 2021, with material from Servier Medical Art. BNIP3: Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3; Drp1: dynamin-related protein 1; Dyn2: dynamin 2; EVs: extracellular vesicles; FIS1: fission 1; FUNDC1: FUN14 domain containing 1; HSP60: heat shock protein 60; IMM: inner mitochondrial membrane; LC3: light chain 3; MFN1/2: mitofusin 1/2; mtHSP70: mitochondrial heat shock protein 70; NIX: Nip3-like protein X; Nrf1/2: nuclear factor E2-related factor1/2; OMM: outer mitochondrial membrane; OPA1: optic atrophy 1; P62: sequestosome-1; PGC-1α: AMPK-proliferator-activated receptor cofactor 1; PINK1: phosphatase-and-tensin-homolog-induced putative kinase 1; SAH: subarachnoid hemorrhage; TFAM: mitochondrial transcription factor A; TNTs: tunneling nanotubes; VDAC: voltage-dependent anion channel.