Neurodegeneration Mechanisms Associated with Coenzyme A Deficiency

Coenzyme A (CoA) is indispensable for cellular metabolism, serving as an acyl-group carrier in hundreds of enzymatic reactions. Deficiencies in CoA biosynthesis, often arising from mutations in pantothenate kinase (PANK) or CoA synthase (COASY), precipitate a cascade of neurodegenerative processes. Impaired CoA availability disrupts mitochondrial energy production and lipid metabolism, compromises the assembly of iron–sulfur clusters and perturbs redox regulation. Mitochondrial iron uptake is reduced, leading to cytosolic iron accumulation, generation of reactive oxygen species and oxidative damage to lipids, proteins and DNA. Concurrently, the collapse of proteostasis arises from inadequate chaperone support and defective autophagic clearance, driving neuronal dysfunction and death. These cellular derangements manifest clinically in syndromes of neurodegeneration with brain iron accumulation (NBIA), characterised by motor impairment, cognitive decline and iron deposition in basal ganglia. Emerging insights reveal that glial cell dysfunction, inflammatory responses and dysregulated vesicular trafficking further amplify pathology. Collectively, these mechanisms underscore CoA deficiency as a nexus linking metabolic failure, iron dysregulation and proteome destabilisation in neurodegenerative disease.

Research from Nature Portfolio

Recent studies have described the development of a brain-penetrant allosteric activator of pantothenate kinase that stabilises the enzyme’s active dimeric form and renders it insensitive to feedback inhibition. Oral administration of this compound in a mouse model of brain CoA deficiency elevated CoA levels in both liver and brain, reversed weight loss, improved locomotor function and extended survival. This work establishes a proof of concept for pharmacologically restoring CoA homeostasis as a therapeutic avenue in inherited neurodegenerative disorders.

Neurodegeneration Mechanisms Associated with Coenzyme A Deficiency publication trend

The graph below shows the total number of articles in neurodegeneration mechanisms associated with coenzyme a deficiency across all publications each year (not limited to Nature Index journals).

Technical terms

Coenzyme A: A central metabolic cofactor that carries acyl groups and participates in energy production, lipid synthesis and redox regulation.

Pantothenate kinase (PANK): The enzyme catalysing the first and rate-limiting step in CoA biosynthesis; mutations lead to reduced CoA levels and neurodegeneration.

Neurodegeneration with Brain Iron Accumulation (NBIA): A group of inherited disorders characterised by iron deposition in basal ganglia, motor impairment and cognitive decline.

Proteostasis: The maintenance of protein homeostasis through balanced synthesis, folding, trafficking and degradation of cellular proteins.

Iron–sulfur cluster: A prosthetic group composed of iron and inorganic sulphur atoms, essential for mitochondrial electron transport and enzymatic activities.

Astrocyte: A type of glial cell in the central nervous system that supports neuronal metabolism, iron handling and synaptic function.

References

1. Mitochondrial iron deficiency triggers cytosolic iron overload in PKAN hiPS-derived astrocytes. Cell Death & Disease (2024).
2. HLH‐30/TFEB Rewires the Chaperone Network to Promote Proteostasis Upon Perturbations to the Coenzyme A and Iron–Sulfur Cluster Biosynthesis Pathways. Aging Cell (2025).
3. A therapeutic approach to pantothenate kinase associated neurodegeneration. Nature Communications (2018).