Vitamin B12 Deficiency and the Nervous System: Beyond Metabolic Decompensation-Comparing Biological Models and Gaining New Insights into Molecular and Cellular Mechanisms

Abstract

Vitamin B12 (VitB12) is a micronutrient and acts as a cofactor for fundamental biochemical reactions: the synthesis of succinyl-CoA from methylmalonyl-CoA and biotin, and the synthesis of methionine from folic acid and homocysteine. VitB12 deficiency can determine a wide range of diseases, including nervous system impairments. Although clinical evidence shows a direct role of VitB12 in neuronal homeostasis, the molecular mechanisms are yet to be characterized in depth. Earlier investigations focused on exploring the biochemical shifts resulting from a deficiency in the function of VitB12 as a coenzyme, while more recent studies propose a broader mechanism, encompassing changes at the molecular/cellular levels. Here, we explore existing study models employed to investigate the role of VitB12 in the nervous system, including the challenges inherent in replicating deficiency/supplementation in experimental settings. Moreover, we discuss the potential biochemical alterations and ensuing mechanisms that might be modified at the molecular/cellular level (such as epigenetic modifications or changes in lysosomal activity). We also address the role of VitB12 deficiency in initiating processes that contribute to nervous system deterioration, including ROS accumulation, inflammation, and demyelination. Consequently, a complex biological landscape emerges, requiring further investigative efforts to grasp the intricacies involved and identify potential therapeutic targets.

Keywords: antioxidants; cellular metabolism; energy balance; metabolic decompensation; nervous system homeostasis; neurodegeneration; nutrients; oxidative stress; vitamin B12.

Figure 1

The diagram illustrates the key mechanisms outlined in the text regarding the absorption, storage, and intracellular metabolism of Vitamin B12 in human beings.

Figure 2

The lack of Vitamin B12 notably impacts MTR or MUT, enzymes reliant on it as a cofactor. This deficiency not only disrupts the biosynthesis of crucial compounds but also triggers the accumulation of reaction intermediates that are potentially toxic at increased concentrations, leading to metabolic decompensation. Lightning bolt icons indicate the metabolic steps that might indirectly contribute to oxidative stress. The light green arrows highlight further biochemical implications resulting from Vitamin B12 deficiency, potentially influencing molecular and cellular processes.

Figure 3

Divergent metabolic processes and uptake mechanisms of Vitamin B12 across human, mouse, and zebrafish. The question mark indicates that the mechanism has been poorly characterized. The arrows in the ‘metabolism’ part of the figure indicate an increase (if pointing upwards) or a decrease (if pointing downwards) in the metabolite or vitamin B12, while the equal sign indicates no change.

Figure 4

Vitamin B12’s functions as an anti-inflammatory agent by binding to CD14 (A), modulating potential energetic metabolism (B), and mediating NMDA receptor-linked excitotoxicity (C).

Figure 5

This outline explores the molecular and cellular changes in the nervous system during Vitamin B12 deficiency, potentially leading to neuroinflammation. It emphasizes that metabolic decompensation is just one facet of this intricate scenario. The question mark indicates that the mechanism has been poorly characterized. The dark blue arrows indicate an increase (if pointing upwards) or a decrease (if pointing downwards) of the compound or of the process.

Figure 6

Many insights into the function of Vitamin B12 have emerged from conditions that commonly deteriorate due to its deficiency. The outline illustrates the more recent findings regarding Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Parkinson’s Disease (PD), and Vitamin B12 deficiency. The question mark indicates that the mechanism has been poorly characterized. The dark blue arrows signify a decrease in CD320. Purple arrows represent involved processes, while the blunt-ended line denotes an inhibitory effect.