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Research progress of mitochondrial dynamic network in sepsis-related encephalopathy
Research progress of mitochondrial dynamic network in sepsis-related encephalopathy. The homeostasis of the mitochondrial network is closely related to the maintenance of mitochondrial function. Although the pathophysiological mechanism of SAE is complicated, mitochondrial dysfunction is still the core.
Mitochondria are the main sites for oxidative phosphorylation and ATP production in eukaryotic cells. They are continuously fused, divided and transported, forming a highly interconnected dynamic tubular network within the cell. The mitochondrial network plays a key role in the energy metabolism of nerve cells. Abnormal mitochondrial dynamic network is an important pathological mechanism of central nervous system diseases. Sepsis is one of the most common fatal causes in ICU, which can induce septic shock and multiple organ dysfunction syndrome.
Sepsis associated encephalopathy (Sepsis associated encephalopathy, SAE) is a common and most serious neurological complication of sepsis. It is characterized by changes in cognitive function and consciousness and is an independent risk factor affecting the prognosis of patients with sepsis. However, there is a lack of effective diagnosis and treatment methods. Current research generally believes that nerve cell energy metabolism disorders are the initial link of SAE.
Therefore, the dysfunction caused by mitochondrial fusion, division and abnormal transport is closely related to the pathogenesis of SAE. This review mainly reviews the role of mitochondrial dynamic network in the occurrence and development of SAE, explains the damage mechanism of SAE based on mitochondrial network homeostasis, and provides research basis for its treatment.
1 The composition of the mitochondrial dynamic network
Mitochondria are highly dynamic organelles in the cell. Through continuous fusion, division and transport, they form an interconnected dynamic network within the cell. They will show different shapes in different cell cycles and growth states, which are essential for accurately regulating the complex life of cells. Activities are required.
Mitochondrial fusion includes the fusion of the outer mitochondrial membrane and the inner mitochondrial membrane. The outer membrane fusion is mediated by the fusion protein Mitofusins, and the inner membrane fusion is mediated by optic atrophy 1, OPA1, both of which participate in the regulation of mitochondrial fusion.
The fusion protein Mitofusins has two subtypes: Mfn1 and Mfn2. Studies have shown that knocking out Mfn1 and Mfn2 will result in the loss of mitochondrial fusion ability and the formation of a large number of mitochondrial fragmentation, characterized by the loss of mitochondrial crest ultrastructure and membrane potential, mitochondrial DNA (mitochondrial DNA, mtDNA) defect, and mitochondrial gene mutation increase.
Mfn1 and Mfn2 are also modulated and regulated by multiple factors. Mfn1 T562 can be phosphorylated by extracellular regulatory protein kinase 2, which inhibits Mfn1 oligomerization, thereby significantly fragmenting mitochondria and promoting neuronal apoptosis; and Mfn2 S442 The spot can be phosphorylated by human PTEN-induced kinase 1, and the phosphorylated Mfn2 becomes the docking site of the E3 ubiquitin ligase parkin on the outer mitochondrial membrane, promoting its autophagy degradation.
In addition, Mfn1 and Mfn2 can form crosslinks through disulfide bonds to resist oxidative stress damage. In short, although Mfn1 and Mfn2 have the same functions, they have their own characteristics: Mfn2 is more tissue-specific in terms of expression time and space. In addition to promoting fusion, it also participates in a variety of signaling pathway cascades, and acts as a pro-apoptosis and proliferation protein. Function; while Mfn1 is more specific in regulating mitochondrial fusion, after purification, GTPase activity is higher, so it has a higher fusion efficiency.
OPA1 first forms a precursor protein in the mitochondrial cytoplasm, and then transports it to the mitochondrial membrane space to play a role. During transport, OPA1 is hydrolyzed by mitochondrial processing peptidase (L‑OPA1). L‑OPA1 can interact with cardiolipin in the inner mitochondrial membrane to promote fusion; L‑OPA1 can also be used by metalloproteinase OMA1/ in the mitochondrial membrane space. YMELL1 is hydrolyzed into short fragments (S-OPA1), and S-OPA1 plays a role in maintaining oxidative phosphorylation, mitochondrial cristae structure and function.
In addition, OPA1 can be modified by post-transcriptional translation. Studies have found that OPA1 can be acetylated under cell stress and fusion is impaired, while silent mating type information regulation 2 homolog-3 (SIRT3) can be Deacetylation of OPA1, thereby protecting the mitochondrial fusion function. Therefore, in addition to its fusion effect, OPA1 also participates in the maintenance of apoptosis, ridge ultrastructure and the stability of the respiratory supercomplex.
Mitochondrial fission refers to the process by which the mitochondrial membrane is broken to redistribute the mitochondrial matrix and its DNA to form two mitochondria. It is composed of dynamin‑related protein 1, Drp1 and mitochondrial adaptor proteins, including mitochondrial fission 1 (mitochondrial fission 1). Protein, Fis1), mitochondrial fission factor (MFF) and mitochondrial dynamics proteins 49 and 51 (MID49/51) interact and participate in the regulation of division.
Drp1 is the main executor of mitochondrial division. It exists in the cytoplasm. After activation, it is recruited by the mitochondrial adaptor protein to the mitochondrial surface to mediate division. Studies have shown that the dominant negative mutation Drp1 can significantly reduce the division of mitochondria, resulting in a continuous long tube-like morphology of mitochondria.
Drp1 gene knockout mice showed dilated heart, delayed cerebellar development, and premature apoptosis of cerebral cortex cells. These features are closely related to the lack of ATP production, swelling of mitochondrial morphology and impaired apoptosis. The activation of Drp1 is regulated by post-translational modifications involved in a variety of factors, and is dominated by phosphorylation of serine at specific sites.
In neurons, calmodulin-dependent protein kinase II can phosphorylate Drp1 at S616, thereby enhancing Drp1 activity and promoting mitochondrial division. The phosphorylation of Drp1 S637 mediated by protein kinase A can inhibit Drp1 activation and mitochondrial division. In addition to phosphorylation, multiple lysine residues on Drp1 can also be modified by small ubiquitination-related modifications, which is conducive to the stabilization of Drp1 oligomers on the outer mitochondrial membrane, thereby promoting mitochondrial division and apoptosis.
Fis1, MFF and MID49/51 are receptor-like proteins located in the outer mitochondrial membrane, which can directly bind to Drp1 and assemble into oligomers to induce mitochondrial division. Lee et al. pointed out that overexpression of Fis1 can cause mitochondrial fragmentation, and inhibition of Fis1 expression can reduce mitochondrial division, while Osellame et al. believe that high expression of Fis1 does not lead to mitochondrial fragmentation.
In addition, Otera et al. found that overexpression of MFF can induce mitochondrial division, while overexpression of MID51 or MID49 can significantly lengthen mitochondria. Therefore, mitochondrial division is multiple pathways mediated by multiple mitochondrial outer membrane receptor molecules, and the specific mechanism needs to be further explored.
1.3 transfer to luck
Mitochondrial transport refers to the dynamic process of intracellular mitochondria moving to a specific area with changes in energy state.
The transport of mitochondria in the cell requires the participation of track, motor protein, and motor adaptor transporter. In mammalian nerve cells, time-lapse imaging can be used to show that mitochondria are transported in two directions along the microtubule orbit.
Studies have shown that motor protein is a multi-subunit complex based on microtubule-mediated mitochondrial transport, which mainly includes kinesin and dynein, and obtains power by hydrolyzing ATP to carry out long-distance positive and negative transport to mitochondria, respectively. The interaction between motor protein and mitochondria is not direct, but indirectly participates in mitochondrial transport through the motor adaptor transporter.
In mammalian neurons, the interaction between the motor adaptor transporter TRAK (trafficking kinesin protein) and the KIF5 in the Kinesin family requires the participation of the RHO family GTPase Miro on the outer mitochondrial membrane, and the three jointly participate in mitochondrial transport.
Studies have shown that the transport of mitochondria along microtubules is a Ca2+ sensitive process. The Miro family acts as a Ca2+ sensor to regulate the interaction between mitochondria and members of the TRAK family of motor adaptor transporters.
In addition, mitochondrial transport is also regulated by related enzymes. Pekkurnaz et al. found that high extracellular glucose can activate O-linked N-acetylglucosamine (O-GlcNAc), and O-GlcNAc can make the neuron The glycosylation modification of TRAK, the key motor protein for mitochondrial transport, leads to the stagnation of mitochondrial transport, which is closely related to the impaired axon function.
2 The significance of mitochondrial dynamic network balance
The balanced fusion/division ratio in the cell and the precise distribution and positioning are inseparable from the stability of mitochondrial function and physiological activity.
When the fusion/division ratio is high in the cell, the mitochondria form an interconnected tubular network, and when the fusion/division ratio is low, the mitochondria form a fragmented form. The mutual diffusion of the matrix during the fusion process is conducive to diluting the mutant mtDNA and oxidized protein. This cross-complementary approach is essential for maintaining the mitochondrial respiratory function and the fidelity of the genome, and improving the ability of mitochondria to resist damage.
Mitochondrial division can cause irreversible damage to mtDNA and depolarized mitochondrial membranes to gather into a sub-mitochondria during division, and further degrade through ubiquitination and autophagy, which is essential for maintaining the stability of mtDNA and mitochondrial membrane potential.
The distribution of mitochondrial subcellular organelles is extremely important for neurons, which are highly polarized cells with complex neural processes. The timely transport and distribution of mitochondria determines the energy supply in areas with high energy demand (such as synaptic ends). If the distribution is abnormal, local synaptic ATP production may be insufficient, so that neurotransmitter synthesis and vesicle circulation are maintained abnormally.
3 Mitochondrial dynamic network and SAE
The weight of brain tissue accounts for 2% to 5% of the body, but oxygen consumption accounts for 25% of the body, and it is rich in lipids. It is prone to oxidative stress damage and mitochondrial dysfunction during sepsis. Current research generally believes that nerve cell energy metabolism disorders are the initiating link of SAE, and mitochondria are the core of energy metabolism, and their dysfunction is the key to the occurrence and development of SAE. The morphology and function of mitochondrial network are closely related. Therefore, dysfunction caused by mitochondrial fusion, division and transport abnormalities is an important pathological mechanism of SAE.
3.1 Changes in mitochondrial network morphology during SAE
Studies have shown that at the initial stage of SAE injury, mitochondria are swollen, mtDNA is damaged and some membranes are depolarized. Mitochondrial fusion promotes complementation between mitochondria, repairs damaged mtDNA, and maintains oxidative phosphorylation; mitochondrial division can cause partial depolarization of membranes and mutations mtDNA accumulates in daughter mitochondria and is further degraded by autophagy.
With the further aggravation of the damage, the mitochondrial electron transport respiratory chain is blocked, ATP synthesis decreases, and the production of reactive oxygen species (ROS) increases. Mitochondrial damage occurs in a cascade of cascades, and excessive ROS continues to drive oxidative stress. At this time, mitochondrial division is enhanced and fusion is damaged, showing widespread fragmentation. A large number of fragmented mitochondria activate apoptosis and necrosis signals, resulting in irreversible damage to the body. This suggests that mitochondrial fusion/division imbalance is closely related to the occurrence and development of SAE.
Moreover, the imbalance of division and fusion will affect mitochondrial transport and even stall mitochondrial transport in neurons. The mitochondria in the neuron cell will be transported to the end of the axon, providing energy for synaptic transmission and vesicle secretion, and fusion repair of the mitochondria with toxic proteins and mutant mtDNA; and the damaged mitochondria will be transported back to the cell body for processing. Repair and supplement or be degraded by lysosome. The study found that after bacterial lipopolysaccharide stimulated mouse brain slices, the transport rate of axon mitochondria decreased, the proportion of resting mitochondria increased, and retrograde mitochondria decreased significantly, which in turn resulted in impaired axon function.
Studies have also found that during sepsis, the hippocampus is susceptible to neuro-inflammatory environment to induce synaptic plasticity defects, leading to cognitive and memory impairment, which suggests that the dynamic network imbalance caused by abnormal mitochondrial transport may mediate SAE through synaptic plasticity. occur.
3.2 Changes in the expression of mitochondrial network-related proteins during SAE
Under physiological conditions, mitochondrial fusion-related proteins Mfn1, Mfn2, OPA1 and division-related proteins Drp1, Fis1, MFF, MID49/51, etc. jointly maintain the size, number, shape and physiological functions of mitochondria.
In SAE, inducible nitric oxide synthase (iNOS) expression is up-regulated, Ca2+ overload and ROS production increase, Mfn2, OPA1 expression decreases, and Drp1 activity increases, which leads to mitochondrial fusion/division imbalance and transport obstruction, which aggravates mitochondria The damage of membrane potential energy, respiratory enzymes and mtDNA eventually leads to neuron damage and dysfunction.
Studies have shown that up-regulation of iNOS expression can increase the synthesis of nitric oxide (NO), and NO in turn S-nitrosylates Drp1 cys644 to enhance Drp1 activity, leading to excessive fragmentation of mitochondria and causing neuronal synapses. Loss and cell death. Studies have also shown that increased ROS in neurons can cleavage the N-terminal of OPA1 and remove residue K301, leading to mitochondrial fragmentation and functional damage, and ultimately neuronal apoptosis; and increased ROS can cause intracellular Ca2+ signal transients and Activation of mitogen-activated protein kinase results in the stagnation of mitochondrial transport and impaired synaptic function.
The down-regulation of OPA1 can cause damage to fusion and fragmentation of mitochondria, which in turn leads to a decrease in mitochondrial respiratory capacity and loss of membrane potential. The decrease in respiratory capacity can lead to the accumulation of low membrane potential mitochondria and further inactivation of OPA1, resulting in impaired mitochondrial function. A vicious circle; and the decrease of Mfn2 expression can weaken the interaction with Miro, resulting in the inhibition of mitochondrial transport in axons.
Finally, in neurons, the decrease in membrane potential after mitochondrial injury can activate the Pink1‑Parkin pathway, which can ubiquitinate Miro Lys27, thereby affecting the transport of mitochondria in neurons. These studies suggest that abnormal expression of mitochondrial dynamic network related molecules in sepsis can directly lead to neuronal apoptosis and brain dysfunction.
Studies have found that Mdivi-1, a mitochondrial division inhibitor, can alleviate brain damage and cell apoptosis in sepsis, and inhibit the release of S100b protein and neuron-specific enolase in plasma.
(source:internet, reference only)