Role of amino acid metabolism in mitochondrial homeostasis

Abstract

Mitochondria are central hubs for energy production, metabolism and cellular signal transduction in eukaryotic cells. Maintenance of mitochondrial homeostasis is important for cellular function and survival. In particular, cellular metabolic state is in constant communication with mitochondrial homeostasis. One of the most important metabolic processes that provide energy in the cell is amino acid metabolism. Almost all of the 20 amino acids that serve as the building blocks of proteins are produced or degraded in the mitochondria. The synthesis of the amino acids aspartate and arginine depends on the activity of the respiratory chain, which is essential for cell proliferation. The degradation of branched-chain amino acids mainly occurs in the mitochondrial matrix, contributing to energy metabolism, mitochondrial biogenesis, as well as protein quality control in both mitochondria and cytosol. Dietary supplementation or restriction of amino acids in worms, flies and mice modulates lifespan and health, which has been associated with changes in mitochondrial biogenesis, antioxidant response, as well as the activity of tricarboxylic acid cycle and respiratory chain. Consequently, impaired amino acid metabolism has been associated with both primary mitochondrial diseases and diseases with mitochondrial dysfunction such as cancer. Here, we present recent observations on the crosstalk between amino acid metabolism and mitochondrial homeostasis, summarise the underlying molecular mechanisms to date, and discuss their role in cellular functions and organismal physiology.

Keywords: TCA cycle; amino acid metabolism; amino acid recycling; lifespan; mitochondrial homeostasis; proteasome; respiratory chain.

FIGURE 1

Cellular regulation of amino acid levels and possible physiological/pathological consequences of amino acid deficiency or excess. The lack of amino acids is sensed by GCN2, which is activated upon binding to an uncharged tRNA. Activated GCN2 phosphorylates eIF2α to prevent translation initiation. Amino acid deficiency decreases mitochondrial membrane potential (low membrane potential indicated in grey, otherwise shown in orange). Excess amino acids are imported and sequestered by the lysosome, activate mTORC1, and induce the formation of MDC and MVB. Amino acid deficiency or amino acid overload in the cell can lead to a variety of diseases.

FIGURE 2

Changes of amino acid metabolism upon TCA cycle and respiratory chain inhibition. The TCA cycle is involved in both catabolism and anabolism of amino acids. The TCA cycle and the respiratory chain are closely linked both physically and functionally. Inhibition of TCA cycle and respiratory chain affect amino acid metabolism.