Arginine Supplementation in MELAS Syndrome: What Do We Know about the Mechanisms?

Abstract

MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists to support this treatment for MELAS. The mechanisms underlying the effect of arginine on MELAS pathophysiology remain unclear, although it is hypothesized that arginine could increase nitric oxide availability and, consequently, enhance blood supply to the brain. A more comprehensive understanding of these mechanisms is necessary to improve treatment strategies, such as dose and regimen adjustments; identify which patients could benefit the most; and establish potential markers for follow-up. This review aims to analyze the existing evidence concerning the mechanisms through which arginine supplementation impacts MELAS pathophysiology and provide the current scenario and perspectives for future investigations.

Keywords: MELAS; arginine; mitochondria; mitochondrial DNA; nitric oxide; oxidative stress.

Figure 1

L-ARG sources and availability. The scheme shows the different sources of L-ARG and the processes that regulate its availability (gray arrow-shaped boxes). Bluish-gray rounded rectangles demonstrate the pathways or enzymes associated with these processes. Endogenous synthesis is performed by the intestinal renal axis with enzymatic steps occurring in the small intestine and kidney (light blue rounded rectangles). The enzymes involved in L-ARG transport and catabolism are shown in bluish-gray rounded rectangles. The red blunt arrow shows arginase inhibition by NOHA. L-CIT, L-citrulline; ASS, argininosuccinate synthase; ASL, argininosuccinate lyase; CAT, cationic amino acid transporter; L-ORN, L-ornithine; NOS, nitric oxide synthase; NOHA, Nω-hydroxy-L-ARG; NO, nitric oxide; ADC, arginine decarboxylase; AGAT, arginine/glycine amidino-transferase.

Figure 2

Key players in stroke-like development and possible effects of L-ARG supplementation. The figure demonstrates the complex connections (black lines) between the players (circles) involved in the development of stroke-like episodes in MELAS. The key players are shown in the brown circles. Other colored circles represent additional players related to oxidative stress (light brown), energy metabolism (blue) and NO pathways (pink). At the bottom, we show the effects of L-ARG supplementation (rounded-corner rectangles) found in different studies. mtDNA, mitochondrial DNA; RC, respiratory chain; suppl, supplementation; CI, Complex I; CIII, Complex III; TCA, tricarboxylic acid; L-CIT, L-citrulline; ROS, reactive oxygen species; NOS, nitric oxide synthase; NO, nitric oxide; NV, neurovascular.