Branched-Chain Amino Acids Metabolism and Their Roles in Retinopathy: From Relevance to Mechanism

Abstract

Retinopathy is one of the leading causes of irreversible blindness and vision loss worldwide. Imbalanced nutrients play important roles in the pathogenesis and pathophysiology of retinal diseases. Branched-Chain Amino Acids (BCAAs), as essential amino acids, perform a variety of biological functions, including protein synthesis, glucose metabolism, lipid metabolism, inflammation, and oxidative stress in metabolic tissues of diabetes and aging-related diseases. Recently, it has been shown that BCAAs are highly related to neuroprotection, oxidative stress, inflammatory and glutamate toxicity in the retina of retinopathy. Therefore, this review summarizes the alterations of BCAA levels in retinopathy, especially diabetic retinopathy and aging-related macular disease, and the genetics, functions, and mechanisms of BCAAs in the retina as well as other metabolic tissues for reference. All of these efforts aim to provide fundamental knowledge of BCAAs for further discoveries and research on retina health based on the sensing and signaling of essential amino acids.

Keywords: branched-chain amino acids; glutamate toxicity; inflammatory; metabolomics; neuroprotection; oxidative stress; retinopathy.

Figure 1

Regulatory factors involved in BCAA catabolism. BCAAs are transported to the cytoplasm by the transporter LAT, then transaminated by BCATc to form BCKA or further transported into mitochondrion by SLC25A44. In the mitochondrion, BCKDK inhibits the activity of BCKDH by phosphorylation, while PPM1K promotes BCKDH activity by dephosphorylation. Eventually, the carbon in BCAAs ends up as CO₂ or metabolites in the tricarboxylic acid cycle (TCA cycle).

Figure 2

The roles of BCAAs in the retina and other major metabolic tissues. BCAAs from protein diets are absorbed by the intestine and exert crucial functions in the retina and tissues, such as liver, muscle, and adipose tissue. The functions of BCAAs in the retina include regulation of glutamate excitatory toxicity, neuroprotection, oxidative stress, and inflammation. In addition, BCAAs, as critical nutrient substances and signaling molecules, are also involved in the regulation of protein synthesis, glucose metabolism, insulin resistance, and energy expenditure.