Propionic acidemia (PA) is a genetic metabolic disorder caused by mutations in the mitochondrial
enzyme,
propionyl-CoA carboxylase (PCC), which is responsible for converting
propionyl-CoA to
methylmalonyl-CoA for further metabolism in the tricarboxylic acid cycle. When this process is disrupted,
propionyl-CoA and its metabolites accumulate, leading to a variety of complications including life-threatening
cardiac diseases and other metabolic
strokes. While the clinical symptoms and diagnosis of PA are well established, the underlying pathophysiological mechanisms of PA-induced diseases are not fully understood. As a result, there are currently few effective
therapies for PA beyond
dietary restriction. This review focuses on the pathophysiological mechanisms of the various complications associated with PA, drawing on extensive research and clinical reports. Most research suggests that
propionyl-CoA and its metabolites can impair mitochondrial energy metabolism and cause cellular damage by inducing oxidative stress. However, direct evidence from in vivo studies is still lacking. Additionally, elevated levels of
ammonia can be toxic, although not all PA patients develop
hyperammonemia. The discovery of pathophysiological mechanisms underlying various complications associated with PA can aid in the development of more effective therapeutic treatments. The consequences of elevated odd-chain
fatty acids in lipid metabolism and potential gene expression changes mediated by
histone propionylation also warrant further investigation.