Dose–response curve depicting the quantitative features of hormesis. NOAEL, No Observed Adverse Effect Level; ZEP, zero equivalent point.

Membrane sphingomyelin and ceramide metabolism pathways involved in adaptive stress responses and neurodegenerative conditions. Modified from Cutler et al. (). FA, fatty acids; ROS, reactive oxygen species; SMase, sphingomyelinase; SPT, serine palmitoyl CoA transferase; TNF, tumor necrosis factor.

The plasma membrane redox system is a conserved sensor of cellular redox status and energy metabolism. Modified from Hyun et al. (). CoQ, coenzyme Q10; ETS, electron transport system; NAD⁺, oxidized nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NAD(P)H, reduced nicotinamide adenine dinucleotide phosphate; NQO1, NAD(P)H quinone oxidoreductase 1.

Cell stress responses. Expression of HS genes including chaperones and components of the clearance machinery is induced in response to physiological and environmental stress conditions, including longevity stimuli, such as fasting, caloric restriction, or polyphenol antioxidants, and protein conformational diseases. HSF1 can also be directly stimulated by longevity stimuli such as the histone deacetylase SIRT1 that directly activates HSF1 by deacetylation, thus fostering longevity. The increased flux of damaged or misfolded proteins in response to proteotoxic environmental conditions (stress) is the trigger for the induction of the cellular stress response. Aging, however, is associated with a gradual decline in potency of the heat shock response and this may prevent repair of protein damage, leading to degeneration and cell death. HSF, heat shock transcription factor; SIRT, silent information regulator two.

SIRT1-based and related hormetic signaling pathways in neurons are coupled to transcriptional regulators that control expression of genes involved in neuronal plasticity and cell death. AMPK, adenosine monophosphate-activated protein kinase; AOE, antioxidant enzyme; BDNF, brain-derived neurotrophic factor; CREB, cyclic AMP response element binding protein; ERK, extracellular signal regulated kinase; ERR, estrogen-related receptor; FH, forkhead transcription factor; HIF, hypoxia inducible factor; JNK, jun N-terminal kinase; PDK, pyruvate dehydrogenase kinase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1α; PPAR, peroxisome proliferator activated receptor; SOD, superoxide dismutase.

Endogenous biosynthetic pathways of (a) NO, involving NOSs, (b) CO, involving HO isoforms (HO-1, HO-2), and (c) H₂S, involving CBS, CSE, and MPST. Methionine, which is derived from alimentary sources, is converted to S-adenosylmethionine by methionine adenosyltransferase. S-adenosylmethionine is subsequently hydrolyzed to homocysteine by glycine N-methyltransferase. Cystathionine β-synthase catalyses the production of cystathionine by transferring serine to homocysteine. Cystathionine γ-lyase, a pyridoxal 5′-phosphate-dependent enzyme, subsequently converts cystathionine to cysteine. In the mitochondria, cysteine can get converted to 3-mercaptopyruvate by aspartate aminotransferase, which can then be converted to H₂S by MPST. CBS, cystathionine β-synthase; CO, carbon monoxide; CSE, cystathionine γ-lyase; HO, Heme oxygenase; H₂S, hydrogen sulfide; MPST, 3-mercaptopyruvate sulfur transferase; NO, nitric oxide; NOS, NO synthase.

The Keap1/Nrf2/ARE pathway. Under basal conditions transcription factor Nrf2 is bound to a cytoplasmic repressor Keap1, which targets Nrf2 for ubiquitination and proteasomal degradation via association with the Cullin 3-based E3 ubiquitin ligase complex. Small molecule inducers modify highly reactive (sensor) cysteine residues of Keap1, which loses its ability to target Nrf2 for degradation. This results in stabilization of Nrf2, binding to the ARE (in heterodimeric combinations with a small Maf transcription factor), and activation of the transcription of cytoprotective (phase 2) genes. ARE, antioxidant response element; Keap1, Kelch-like ECH-associated protein 1; Nrf2, nuclear factor-erythroid 2 p45-related factor 2.

Overall structures of Nrf2 and Keap1 showing the different domains. In Nrf2, the DLG motif (amino acids 27–32) and the ETGE motif (amino acids 77–82) of the Neh2 domain comprising the two Keap1-binding sites are indicated and the black bars represent the lysine residues that are ubiquitinated by Cul3-Rbx. The Neh1 and Neh3 domains form the DNA-binding site of the transcription factor. In Keap1, the BTB domain is the dimerization domain and the site of interaction with Cul3. The Kelch domain is the Nrf2-binding domain. The black bars indicate the distribution of the cysteine residues of Keap1.

Chemical structures of inducers of the Keap1/Nrf2/ARE pathway for which neuroprotective activities have been demonstrated.

Regulatory systems in mitochondria and the endoplasmic reticulum involved in hormetic responses of neurons to a range of environmental factors. Modified from Mattson et al. (). CytC, cytochrome c; ER, endoplasmic reticulum; GRP, glucose regulated protein; PTP, permeability transition pore; RyR, ryanodine receptor; SERCA, sarco endoplasmic reticulum calcium ATPase; TCA, tricarboxylic acid cycle; UCP, uncoupling protein; VDAC, voltage-dependent anion channel.

Damaged or misfolded proteins titrate away heat shock proteins that are bound to HSF1 and maintain it in a repressed state before stress, resulting in its activation. Multistep activation of HSF1 involves posttranslational modifications, such as hyperphosphorylation and deacetylation, which allow HSF1 to trimerize and translocate into the nucleus, where inducible acetylation, phosphorylation, and sumoylation occur before binding of nuclear-localized trimers to DNA, and HS genes are transcripted. In particular, upon activation, HSF1 is transiently sumoylated on lysine 298, which requires the phosphorylation of serine 303 adjacent to the consensus site (). Hence, small ubiquitin-related modifier modification is elaborately regulated, and the small ubiquitin-related modifier substrate specificity can be determined by regulatory elements outside the consensus site. Hsp, heat shock protein.

Schematic signal transduction pathways underlying the interfunctional role of CO, NO, and H₂S in the modulation of cell survival. NO exerts neuroprotection through stimulation of the sGC/cGMP/PKG system as well as through S-nitrosylation. As a consequence of S-nitrosylating reactions, inhibition of NFκB and caspase-3 activity and a decrease in cell death occur. NO-mediated transcriptional activation of the Keap1/Nrf2/ARE pathway, associated with activation of K_Ca++ channel and inhibition of mitochondrial energy transductions at level of complex IV (Cox), activates mitochondrial-dependent H₂O₂-mediated redox signaling, leading to upregulation of pro-survival mechanisms, such as vitagenes HO-1 and heat shock protein 70, Bcl2, and mitochondrial biogenesis. The latter results from activation of coactivator PGC-1α and mtTFA. CO-mediated activation of mitochondrial redox signaling results in antiinflammatory, antiproliferative, and antiapoptotic effects, which confer neuroprotection. This occurs through activation of multiple pathways, including PPARγ, PGC-1α, and mtTFA, which induce mitochondrial biogenesis; P38 MAPK, HIF1α, K_Ca++ channel, PI3K-Akt, and Nrf2, as well as inhibition of ERK-1/2. H₂S is a highly reactive, strong reducing molecule that easily reacts with ROS and RNS, thus providing antioxidant activity and, in addition, activates ATP-sensitive potassium channels. Known cellular targets of H₂S include cytochrome c oxidase (complex IV, Cox) and carbonic anhydrase (CA). This gas H₂S has also been demonstrated to regulate cellular signal transduction pathways, including thioredoxin reductase, HO-1, and glutamyl-cysteine synthetase, resulting in cytoprotection. K_ATP, ATP-dependent K⁺; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase.

The ubiquinone (Q) cycle is initiated when one electron from ubiquinol (QH2) is donated to the Rieske-iron sulfur protein and the second electron is donated to cytochrome b. The intermediate moiety is the free radical ubisemiquinone (Qo), which can donate electrons to molecular oxygen to generate superoxide. Mitochondrial electron transport chain generates superoxide at complexes I, II, and III. Complexes I and II generate superoxide within the mitochondrial matrix. Complex III can generate superoxide in both the intermembrane space and the matrix. Release of superoxide from complex III into the cytosol is followed by conversion to H₂O₂ and subsequent activation of oxidant-dependent (redox) signaling pathways, which results in preconditioning. R-FeS, Rieske-iron sulfur.