Mitochondrial energy metabolism and redox signaling in brain aging and neurodegeneration

Abstract

Significance: The mitochondrial energy-transducing capacity is essential for the maintenance of neuronal function, and the impairment of energy metabolism and redox homeostasis is a hallmark of brain aging, which is particularly accentuated in the early stages of neurodegenerative diseases.

Recent advances: The communications between mitochondria and the rest of the cell by energy- and redox-sensitive signaling establish a master regulatory device that controls cellular energy levels and the redox environment. Impairment of this regulatory devise is critical for aging and the early stages of neurodegenerative diseases.

Critical issues: This review focuses on a coordinated metabolic network-cytosolic signaling, transcriptional regulation, and mitochondrial function-that controls the cellular energy levels and redox status as well as factors which impair this metabolic network during brain aging and neurodegeneration.

Future directions: Characterization of mitochondrial function and mitochondria-cytosol communications will provide pivotal opportunities for identifying targets and developing new strategies aimed at restoring the mitochondrial energy-redox axis that is compromised in brain aging and neurodegeneration.

FIG. 1.

Regulatory device encompassing the coordinated interactions of mitochondrial function and redox-sensitive signaling and transcription. PI3K, phosphatidylinositol 3-kinase; Akt, Protein kinase B; MAPK, mitogen-activated protein kinases; Nrf2, nuclear factor erythroid 2-related factor.

FIG. 2.

Metabolism of pyruvate and ketone bodies by brain mitochondria. Glucose is the primary fuel for the brain and the secondary fuel for ketone bodies; metabolism of pyruvate (from glucose) is regulated by the PDH complex; metabolism of ketone bodies requires the activity of succinyl-CoA transferase (SCOT) (which is expressed in brain mitochondria). Acetyl-CoA, generated by PDH or SCOT activities, is further oxidized in the tricarboxylic acid cycle with the formation of NADH. The arrows indicate protein post-translational modifications found in the brain as a function of age: (a) phosphorylation (inactivation) of PDH on the translocation of JNK to the outer mitochondrial membrane (263, 264); (b) and (c) the nitration of SCOT and F₁-ATPase, respectively on the diffusion of ^.NO to the mitochondria due to the increased expression and activity of nNOS as a function of age (137). PDH, pyruvate dehydrogenase; SCOT, succinyl-CoA:3-oxoacid Co-A transferase.

FIG. 3.

The mitochondrial energy-redox axis. Energy–The energy-transducing capacity of mitochondria entails the flow of reducing equivalents (NADH) through the ETC to generate a proton motive force and ATP; the electron leak accounts for 2%–3% of O₂ consumed in the form of O₂^.−and H₂O₂. Redox–Reduction of H₂O₂ to H₂O (and maintenance of a mitochondrial [H₂O₂]_ss is accounted for by thiol-based systems, for which the ultimate reductant is NADPH. Sources of NADPH in brain mitochondria: NNT, IDH2, and ME. GPx1, glutathione peroxidase-1; GPx4, glutathione peroxidase-4 or phospholipid hydroperoxides glutathione peroxidase (in intermembrane space); GR, glutathione reductase; GSTκ, glutathione transferase class kappa; IDH2, isocitrate dehydrogenase-2; ME, malic enzyme; NNT, nicotinamide nucleotide transhydrogenase; Prx3, peroxiredoxin 3; Prx5, peroxiredoxin 5; TCA, tricarboxylic acid; TrxR, thioredoxin reductase.

FIG. 4.

Oxidative conditions and the PI3K/Akt pathway of insulin signaling. The large number of cysteinyl moieties in the IR and IRS renders them susceptible to oxidation (and activation) by H₂O₂; Akt is also redox sensitive. In NIH/3T3 cell lines, Akt translocation to the mitochondria is associated with a second phosphorylation, which is dependent on the mitochondrial [H₂O₂]_ss (7); in neuroblastoma cells, the translocation of Akt to mitochondria resulted in the phosphorylation of a mitochondrial constitutive form of GSK3β and of ATPase (23). IGF-1, insulin-like growth factor-1; IRS, insulin receptor substrate.

FIG. 5.

Oxidative stress-induced activation (bisphosphorylation) of JNK and its translocation to the mitochondrion. Anisomycin or H₂O₂ (via MLK7 or MKK4, respectively) leads to the bisphosphorylation of JNK, which translocates to the outer mitochondrial membrane and triggers a phosphorylation cascade (including PDK2 activity) that results in phosphorylation (inactivation) of the pyruvate dehydrogenase complex (PDH) (263, 264). JNK, c-Jun N-terminal kinase.

FIG. 6.

The mitochondrial energy-redox axis in mitochondrial biogenesis and mitochondrial dynamics. Activation of the co-activator PGC1α requires phosphorylation and deacetylation, pathways involving AMPK and Sirt1; the former is sensitive to the energy levels (expressed as [ATP]/[AMP]+[ADP], whereas the latter requires NAD⁺ as a co-substrate. Changes in the regulators of fission/fusion impinge on the mitochondrial energy-transducing capacity (see text). AMPK, 5′ adenosine monophosphate-activated protein kinase; Drp1, dynamin-related protein 1; OPA, optic atrophy; PGC-1, peroxisome-proliferator-activated receptor γ coactivator-1.