Table 1.
S-Glutathionylated (PSSG) & S-Nitrosylated (PSNO) mitochondrial proteins or proteins interacting with mitochondria in AD, PD, ALS and FRDA.
| Protein | Biological Function |
PSSG | PSNO | Disorder | PSSG/PSNO Effect |
Ref. |
|---|---|---|---|---|---|---|
| α-Ketoglutarate dehydrogenase (KGDH) (E2 subunit) |
Catalyzes the conversion of α-ketoglutarate to succinyl-CoA producing NADH directly providing electrons for the respiratory chain. | + | AD | Impairs glucose utilization. Decreases ATP & ROS production. Decreases rate of mitochondria respiration. |
[132,142] | |
| human Branched- chain aminotransferase protein (hBCAT) (CXXC motif) |
Catalyzes reversible transamination of the α-amino group of the branched-chain amino acids to α-ketoglutarate, forming their respective branched chain α-keto acids and glutamate. | + | AD | Colocalizes with MIA40 & PDI in mitochondria. Role in Aβ misfolding. |
[138,139] | |
| Aβ (Not mitochondrial) (M35 residue) |
Highly oxidized residue of Aβ which affects Aβ conformation. | + | AD | Lipid peroxidation, formation of amyloid plaques & neurofibrillary tangles. Also, correlated with mitochondria dysfunction. | [136] | |
| Tau (Not mitochondrial) (C-terminal microtubule-binding region) |
Microtubule-associated protein, forms insoluble filaments that accumulate as neurofibrillary tangles in AD. | + | AD | Increases tau dimerization & mitochondria dysfunction. | [140,141] | |
| Mn superoxide dismutase (SOD2) | Manganese superoxide dismutase is the essential mitochondrial antioxidant enzyme that detoxifies the free radical superoxide, the major by-product of mitochondrial respiration. |
+ | AD | Inhibit its detoxifying capacity leading to mitochondrial dysfunction |
[143] | |
| Voltage-dependent anion-selective channel protein 1 (VDAC1) |
VDACs promote mitochondrial transport of calcium ions. Part of the mitochondrial permeability transition pore (MPTP), facilitate cytochrome c release, leading to apoptosis. Interact with pro- & anti-apoptotic proteins at the outer mitochondrial membrane. |
+ | AD | Impaired Ca+2 transfer to mitochondria. Decreased ATP levels. |
[30,144] | |
| Voltage-dependent anion-selective channel protein 2 (VDAC2) |
+ | AD | Interaction TUBA-1A, 1B chain and TUBB-2C leading to impaired microtubes architecture. Impaired Ca+2 transfer to mitochondria. |
|||
| Dynamin-related protein 1 (DRP1) (Cys644) |
Facilitates fission, promoting cytochrome c release and apoptosis. | + | AD | Increases mitochondria fragmentation leading to bioenergetics deficits & neuronal damage. | [145,146] | |
| Cyclin-dependent kinase 5 (CDK5) (Cys83, Cys157) |
Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation. It is involved in apoptotic cell death in neuronal diseases (AD, PD) by triggering abortive cell cycle re-entry. | + | AD | Triggers Aß-mediated dendritic spine loss and neuronal damage. Transnitrosylates Drp1 increasing mitochondria fragmentation. | [147] | |
| Succinate dehydrogenase (ubiquinone) flavoprotein subunit | Essential for assembly & activity of succinate dehydrogenase (TCA cycle). | + | AD | Unknown effect * | [148] | |
| Succinyl-CoA ligase (ADP-forming) subunit beta |
Essential for assembly & activity of succinate synthase (TCA cycle). | + | AD | Unknown effect * | [148] | |
| Acyl carrier protein (ACP) | Co-factor of fatty acid biosynthesis. | + | AD | Unknown effect * | [148] | |
| Succinyl-CoA: 3-ketoacid coenzyme A transferase 1 | Transfers coenzyme A (CoA) from a donor thiol ester species (succinyl-CoA) to an acceptor carboxylate (acetoacetate), and produces acetoacetyl-CoA which is further metabolized to enter TCA cycle. | + | AD | Unknown effect * | [148] | |
| NFU1 iron–sulfur cluster scaffold homolog | Critical of iron–sulfur cluster biogenesis. | + | AD | Unknown effect * | [148] | |
| Pyruvate carboxylase (PC) | Catalyzes the conversion of pyruvate to oxaloacetate replenishing TCA cycle intermediates. Participates in gluconeogenesis, lipogenesis & neurotransmitter synthesis. | + | AD | Unknown effect * | [148] | |
| Complex I (CI) (75-kDa subunit) |
Constituent of electron transport chain. First rate-limiting enzyme. | + ** | PD | Inhibits mitochondrial respiration. Induces mitochondria damage and neuronal death. | [149] | |
| PARKIN (RING & IBR domains) |
Ubiquitin E3 ligase which is stratified by PINK1 in outer mitochondrial membrane to promote mitophagy. | + | PD | Mitochondrial dysfunction, protein misfolding and ubiquitin-proteasome system (UPS) impairment. SNO effect inhibits its activity to suppress DRP1-mediated fission. DJ1 activation is essential for PARKIN-SNO. |
[150,151,152] | |
| ATP synthase (β subunit) |
Part of membrane-bound ATP synthase complex. Role in catalytic sites. | + | PD | Impaired mitochondrial function. | [153] | |
| Protein deoxyglycase (DJ1) (Cys53, Cys106) |
Multifunctional protein: chaperone, scavenger of ROS, regulator of transcription & cell signaling. Its gene PARK7 is mutated in familial PD. | + | PD | Increased proximity with CI. Increase apoptosis by impairing BCL- xL function in outer mitochondrial membrane | [154,155,156] | |
| PTEN-induced kinase 1 (PINK1) (Cys568) |
Mitochondrial-targeted serine/threonine-protein kinase encoded by the PINK1 gene which is mutated in familial PD. Protects from ROS by stratifying PARKIN & triggering mitophagy. | + | PD | Inhibits its kinase activity impairing PINK1/PARKIN-mediated mitophagy leading to dopaminergic neuronal cell death | [157] | |
| Myocyte enhancer factor-2 (MEF2) (Not mitochondrial) (Cys39) |
Transcriptional factor with key role in development of multiple organs. | + | PD | Inhibits MEF2-PGC1a transcriptional network, resulting in mitochondrial dysfunction and apoptosis. | [158] | |
| Peroxiredoxin 2 (PRX2) (Cys51, Cys172) |
Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide & organic hydroperoxides to water and alcohols, accordingly. | + | PD | Diminishes peroxidase activity causing hydrogen peroxide to accumulate, exacerbating oxidative stress. | [159] | |
| Prohibitin (PHB) | Mitochondrial chaperone protein | + | PD | Enhances its neuroprotective roles against ROS & glucose deprivation stress. | [160] | |
| alpha-Synuclein (α-Syn) (Tyr39) |
Pre-synaptic neuronal protein implicated in familial and sporadic PD pathogenesis. | ** | PD | α-Syn nitration can potentiate a-synuclein oligomer formation. Extracellular α-Syn oligomers induce ROS/RNS-mediated nitrosylation of PARKIN leading to impaired mitophagy. |
[161,162] | |
| Cu-Zn Superoxide dismutase (SOD1) (mutated & wild type) (Cys111) |
Major cytosolic antioxidant enzyme (with denitrosylase activity). It has been found in mitochondrial matrix. It is genetically & neuropathologically implicated in AD, PD and ALS. | + | ALS | Triggers SOD1 dimer disassembly, aggregation, loss of activity & neuronal damage. Triggers conformational changes in BCL2 & thus cytochrome c release and eventually apoptosis. |
[163] | |
| Protein disulfide isomerase (PD1) (Trx-like catalytic domain CXXC) |
Multifunctional protein which associates with SOD1 misfolding. It is genetically & neuropathologically implicated in ALS. | + | + | ALS | Inhibits its activity, triggers mutant SOD1 aggregation and increases neuronal cell death | [142] |
| α-Ketoglutarate dehydrogenase (KGDH) E2 subunit |
Catalyzes the conversion of α-ketoglutarate to succinyl-CoA producing NADH directly providing electrons for the respiratory chain. Constituents of electron transport chain. |
+ | ? *** | FRDA | Its glutathionylation limits the production of NADH and the electron flow in the respiratory chain | [55,164] |
| Complex III, Complex IV |
Maintains cellular iron homeostasis. It is required for mitochondrial iron supply & function. | + | ? *** | FRDA | Impairs mitochondrial respiration. | [164] |
| Iron regulatory protein 2 (IRP2) (Cys178) |
+ | FRDA | Malfunction of iron homeostasis through UPS-dependent degradation of IRP2 that results in increased accumulation of iron inside the iron storage protein ferritin. | [165,166] |
* These mitochondrial NOS2-dependent S-nitrosylation targets were identified by the proteomic analyses of synaptosomes derived from aged or APP/PS1 mice. The effect of S-nitrosylation on these proteins and their roles in AD pathogenesis is still elusive. ** Complex I can be both S-nitrosylated and nitrated, whereas α-synuclein can only be modified by nitration. *** It has not yet been elucidated whether these proteins are affected by NO-mediated S-nitrosylation in FRDA.4.1.4. GSTs Diverse Roles in Alzheimer’s Disease.