Glycine cleavage system H protein, mitochondrial

GCSH (glycine cleavage system H protein, mitochondrial) is a 18.9 kDa protein that functions as a key component of the glycine cleavage system, shuttling the methylamine group of glycine from the P protein (GLDC) to the T protein (GCST) (UniProt: P23434). The protein also has a pivotal role in lipoylation of mitochondrial enzymes involved in cellular energetics, including components of the pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes. Pathogenic variants in GCSH cause multiple mitochondrial dysfunctions syndrome 7 (MMDS7), an autosomal recessive disorder characterized by glycine accumulation in cerebrospinal fluid and a broad clinical spectrum ranging from neonatal glycine encephalopathy to developmental delay and seizures.

In Alzheimer's Disease, GCSH expression is significantly upregulated in post-mortem human AD brain tissue compared to age-matched controls, with a mean log2 fold-change of 0.28 across subcellular fractions (Chaparral AD proteomics). This elevation suggests a potential compensatory or disease-related shift in glycine metabolism and mitochondrial protein lipoylation during AD neurodegeneration.