Electron Donors

Electron Transport Chain (ETC)

Vitamin C
Ascorbate Anion

NADH
Nicotinamide Adenine Dinucleotide

FADH2
Flavin Adenine Dinucleotide

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Role of iron-sulfur (Fe-S) clusters in OxPhos
OxPhos is the metabolic pathway that produces ATP, the cell's energy currency, using the electron transport chain (ETC) in the inner mitochondrial membrane. Fe-S clusters are essential cofactors in several ETC complexes:
Electron transfer: Fe-S clusters serve as redox centers that facilitate electron transfer within Complexes I, II, and III of the ETC.
Enzyme function: The presence or absence of Fe-S clusters regulates the function of various metabolic enzymes, including those in the citric acid cycle.
Synthesis pathway: The assembly of Fe-S clusters primarily occurs in the mitochondria through a highly conserved process involving scaffold proteins and cysteine desulfurases.

The role of ascorbate (vitamin C) Ascorbate directly supports the availability of iron, a key component of Fe-S clusters. Reduces iron: Ascorbate enhances cellular iron uptake by reducing ferric iron ((Fe^{3+})) to the more bioavailable ferrous form ((Fe^{2+})).Mobilizes iron: It helps mobilize iron from storage proteins like ferritin and from endosomes during the transferrin-dependent uptake cycle.Protects from oxidation: While its reducing activity is vital for iron delivery, ascorbate also functions as an antioxidant, mitigating oxidative stress that can damage the delicate Fe-S clusters.

The biosynthesis of functional Fe-S clusters depends on the synergistic action of these various metabolic pathways: Iron delivery: Ascorbate promotes the uptake and mobilization of ferrous iron ((Fe^{2+})) to the mitochondria, making it available for Fe-S cluster assembly.Sulfur supply: MSM contributes to the overall sulfur pool in the body, providing a source of sulfate that can be converted into cysteine.Cluster assembly: The ISC (Iron-Sulfur Cluster) machinery within the mitochondria uses the iron delivered with the help of ascorbate and the sulfur derived from cysteine to assemble new Fe-S clusters.Integration into OxPhos: Once assembled, the clusters are inserted into the ETC complexes, enabling the electron transfer necessary for oxidative phosphorylation to produce ATP.

Ascorbate oxidation (ATox) is the chemical process by which the antioxidant ascorbate (the dominant form of vitamin C at physiological pH) is oxidized. This process is central to ascorbate's function as a biological antioxidant, as it readily donates electrons to neutralize free radicals, becoming oxidized in the process.

Irreversible degradation: If not recycled back to ascorbate, DHA can undergo an irreversible hydrolysis and be degraded. One of the products of this process is oxalate, a component of kidney stones, which has been linked to high doses of vitamin C.

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L-ascorbic acid as an electron and hydrogen donor

The function of L-ascorbic acid as a reductant (reducing agent) is central to its biological roles, including its action as a vitamin and an antioxidant.

Biological Significance

In living organisms, L-amino acids are the building blocks of proteins. D-amino acids are rarely found in proteins but have specific roles in certain biological processes.

D-amino acids in amyloid plaques

Aging and racemization:

Over time, normal L-amino acids in proteins and peptides can undergo racemization, converting to their D-stereoisomers.

Amyloid beta (Aβ) aging:

This process of aging and racemization affects the amyloid-beta (Aβ) peptides that aggregate to form amyloid plaques. The conversion of L-aspartic acid to D-aspartic acid, for instance, has been linked to changes in the aggregation rate of Aβ peptides.

Presence in plaques:

Studies analyzing the core peptides of amyloid plaques have found a significant percentage of D-amino acids, indicating that this aging process occurs within these pathological deposits.

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Glutamate stimulates the release of ascorbate (vitamin C) from astrocytes in the brain, which can then participate in electron transfer processes like scavenging free radicals and directly influencing neurotransmission. This dynamic interaction is crucial because ascorbate's electron-donating ability helps to regulate glutamate signaling, potentially protecting the brain from neurodegenerative conditions like Alzheimer's disease.

In the brain, ascorbate acts as an electron and hydrogen donor, modulating glutamate signaling in a process of chemical exchange between neurons and glial cells. This interaction helps regulate glutamate uptake and provides neuroprotection against excitotoxicity, which is a key process in many neurodegenerative diseases.

The ascorbate-glutamate exchange

A crucial aspect of the ascorbate-glutamate relationship is the "ascorbate-glutamate heteroexchange" system.