Table 1 Problems caused by mitochondrial dysfunction in CNS diseases

Mitochondria ETC dysfunction

Damage to mitochondrial CI-V results in decreased ATP levels. The absence of NCLX causes protein misfolding and pathological changes in tau protein levels. The Aβ protein forms permeable pores in the Ca²⁺ membrane, promoting Ca²⁺ influx and leading to excessive mitochondrial calcium uptake, which subsequently produces mtROS

AD

[4, 22,23,24]

The inhibition of mitochondrial CI and CIII functions results in a loss of resistance to mPTP-induced neurotoxicity. α-Syn aggregates bind to and activate the SERCA pump, causing Ca²⁺ to flow from the cytoplasm into the ER, thereby inducing mitochondrial degradation

PD

[25,26,27,28,29,30]

Ca²⁺ homeostasis is disrupted, and TDP-43 interferes with the exchange of Ca²⁺ between the ER and mitochondria, leading to decreased mitochondrial Ca²⁺ levels and reduced respiratory chain activity

ALS

[31,32,33,34,35]

The failure of the sodium pump, calcium pump, and other ATP-dependent ion transporters inhibits Ca²⁺ excretion, resulting in calcium overload and extracellular glutamate accumulation. K⁺ efflux commonly triggers NLPR3 activation, further inducing excitotoxicity

IS

[36,37,38,39]

Disturbances in cytosolic Ca²⁺ cycling (the shuttling process between ER and mitochondria) lead to the loss of mitochondrial CI

HD

[24]

Demyelination leads to the transfer of dysfunctional mitochondria from the cell body to the axon, promoting oxidative damage, increasing energy expenditure, altering the calcium balance, and reversing manipulation of the Na⁺/Ca²⁺ pump further aggravates the damage to demyelinated axons

MS

[6, 40]

Production of mtROS

Abnormal ROS signaling and excessive ROS production during ALS progression, significantly promoted muscle atrophy

ALS

[41]

OS -induces the hyperphosphorylation of tau proteins through the inactivation of protein phosphatases 1 and 2A, leading to the abnormal aggregation of tau proteins. Tau protein phosphorylation can activate VGCC, causing mitochondrial Ca²⁺ homeostasis imbalance. Aβ forms calcium permeable pores on the plasma membrane, leading to the accumulation of calcium in the cytoplasm and causing excessive uptake of calcium by mitochondria, thereby promoting further accumulation of mtROS

AD

[42,43,44,45]

The accumulated succinic acid is rapidly oxidized by SDH, while ATP synthesis has not yet returned to normal levels, leading to the accumulation of electrons and protons. This promotes CI reversal, generating mtROS, which cause mitochondrial dysfunction

IS

[5]

The oxidative metabolism of dopamine or the misfolding of proteins such as Parkin and α-Syn can lead to excessive production of mtROS. The generation of mtROS can damage the substantia nigra, leading to the oxidation of DNA, proteins, and lipids. Superoxide rapidly interacts with nitric oxide to produce excess nitrite, which inhibits dopamine biosynthesis

PD

[25, 46, 47]

Mitochondrial stress-induced protein oxidation is more severe than lipid oxidation in SCI

SCI

[48]

Secondary injury related to mitochondrial OS, inflammation, and excitotoxicity

ICH

[49, 50]

Cell apoptosis and pyroptosis

α-Syn regulates the release of substances such as CytC and BCL2 family proteins by increasing the expression of the MT-CO2 gene, thereby impairing the bioenergetics of dopaminergic neuron

PD

[29]

A significant increase in ROS levels leads to alterations in mitochondrial axonal transport, structure, and dynamics, ultimately inducing cell apoptosis

ALS

[51]

Inflammatory caspase-1 and caspase-4/5/11 are activated by pathogenic invasion in the classical pathway

IS

[52]

The NLRP3-pyroptosis signaling pathway of the endoplasmic reticulum is activated. These inflammatory processes specifically sever the intermediate junction between the amino-terminal gsdmin-n and the carboxy-terminal GSDMD, ultimately leading to inflammatory cell death or pyroptosis

ICH

[53, 54]

Aβ fibers induce the formation of NLRP1 inflammatory factors in neurons, thereby inducing caspase1-dependent cell death

AD

[55]

Caspase-1 can also be detected in microglia in demyelinating lesions and normal white matter

EAE

[56]

Inflammatory response

The inflammatory activation of microglial NLRP3 is a key factor in neuroinflammation

ALS

[51]

Aβ or tau proteins can regulate the cleavage and maturation of pro-inflammatory cytokines, including IL-1β and IL18, which participate in tau protein hyperphosphorylation in AD and exacerbating neuroinflammation

AD

[57,58,59,60,61,62]

Dying neurons release synucleins that activate the NLRP3 inflammasome in human blood mononuclear cells. Along with the activation of GSK-3β, proteins in the typical Wnt signaling pathway upregulate death signaling proteins such as caspase3 and CytC through dynamic interactions, promoting dopaminergic neuron degeneration and the activation of glial cells

PD

[63,64,65,66]

Middle cerebral artery thrombosis activates the NLRP1 inflammasome in neurons

IS

[67,68,69,70,71]

An increase or decrease in GSK-3β activity can exacerbate cell death induced by epileptic seizures, which may be due to the differential expression of downstream targets of activated GSK-3β

Epilepsy

[72, 73]

When TBI reduces p-Akt levels and increases GSK-3β, thus increasing the release of caspase3 and other substances, leading to neuronal death

TBI

[74]

SCI reduces the ratio of phosphorylated GSK-3β to total GSK-3β (p-GSK-3β/t-GSK-3β ratio) and increases the number of apoptotic cells in the spinal dorsal horn

SCI

[75]

Mitochondrial dynamics

PGC-1α protein expression decreased. Over-expression of Drp1 and loss of Mfn2 induced by overexpressed α-Syn oligomers and fibroblasts lead to impaired mitochondrial transport in the substantia nigra and striatal dopaminergic neurons

PD

[76,77,78]

A decrease in PGC-1α expression is accompanied by a decrease in mitochondrial antioxidant and uncoupling protein (UCP) expression, which can lead to functional damage to mitochondria in gray matter

MS

[79]

PGC-1α and transcription factor ERRα in microglia synergistically regulate ULK1 to promote autophagy and mitosis, thereby reducing ROS production and inflammasome activation, inhibiting microglia mediated neuroinflammatory responses

IS

[80,81,82]

ApoE-4 reduces PGC-1α levels, SIRT3 damages mitochondria by impairing mitochondrial biogenesis or directly or indirectly reducing the levels of fusion and mitogenic proteins, and tau inhibits parkin translocation to mitochondria, consequently impairing mitochondrial phagocytosis. Also, the expression of Drp1 and Fis1 was higher in the posterior hippocampus, whereas the expression of Mfn1 and Opa1 gradually decreased

AD

[83,84,85,86,87,88,89]

The expression of Mfn1/2 and Opa1 decreases

SAH

[90, 91]

The expression of Drp1 and Fis1 was higher, whereas the expression of Mfn1 and Opa1 gradually decreased

ALS

[92]