Inherited Disorders of Coenzyme A Biosynthesis: Models, Mechanisms, and Treatments

Abstract

Coenzyme A (CoA) is a vital and ubiquitous cofactor required in a vast number of enzymatic reactions and cellular processes. To date, four rare human inborn errors of CoA biosynthesis have been described. These disorders have distinct symptoms, although all stem from variants in genes that encode enzymes involved in the same metabolic process. The first and last enzymes catalyzing the CoA biosynthetic pathway are associated with two neurological conditions, namely pantothenate kinase-associated neurodegeneration (PKAN) and COASY protein-associated neurodegeneration (CoPAN), which belong to the heterogeneous group of neurodegenerations with brain iron accumulation (NBIA), while the second and third enzymes are linked to a rapidly fatal dilated cardiomyopathy. There is still limited information about the pathogenesis of these diseases, and the knowledge gaps need to be resolved in order to develop potential therapeutic approaches. This review aims to provide a summary of CoA metabolism and functions, and a comprehensive overview of what is currently known about disorders associated with its biosynthesis, including available preclinical models, proposed pathomechanisms, and potential therapeutic approaches.

Mitochondrial iron deficiency triggers cytosolic iron overload in PKAN hiPS-derived astrocytes

“…It is clear that brain iron accumulation is a characteristic of many neurodegenerative pathologies, including the most widespread disorders, such as Alzheimer’s disease and Parkinson’s disease [ 9 , 36 ]; however, the specific mechanism of iron deposition and its contribution to neuronal death are not yet fully understood [ 9 ]. In particular, the relationship between CoA biosynthesis defects and brain iron accumulation in PKAN disorders has not yet been elucidated [ 37 ].…”

Patient-Derived Cellular Models for Polytarget Precision Medicine in Pantothenate Kinase-Associated Neurodegeneration

“…Although clinical trials with several compounds are in progress, PKAN treatments primarily aim to control the main disease symptoms: spasticity, seizures, dystonia, or psychiatric disorders [124]. Nevertheless, several promising therapeutic approaches are currently in progress [12,91]. These treatments can be summarized in four categories: (1) iron chelation to eliminate iron accumulation in the brain; (2) metabolite supplementation to correct metabolic deficits in the CoA pathway; (3) PANK isoforms activation to restore CoA biosynthesis; and (4) gene therapy by introducing the wild-type PANK2 gene.…”

“…However, some of these therapies have not been successful, whereas others are under evaluation. For a detailed updated of current PKAN treatment approaches see [12,91,124,125].…”

“…The main mechanism for controlling PANK2 activity is through allosteric inhibition by acetyl-CoA and CoA thioesters [11]. Recently, Cavestro et al have reviewed CoA biosynthesis and degradation pathways [12].…”

Direct single-molecule detection of CoA-SH and ATP by the membrane proteins TMEM120A and TMEM120B

“…As critical components in cellular metabolism, COA-SH and ATP are strongly linked to cell growth, death, and energy provision. 19,20 Abnormal levels of these molecules in the body closely correlate with various diseases, 21 such as cardiovascular diseases, 22 Parkinson's disease, 23 and Alzheimer's disease. 24 Therefore, the development of point-of-care testing (POCT) sensors capable of directly and accurately detecting COA-SH and ATP holds significant importance.…”