Transporters at the Interface between Cytosolic and Mitochondrial Amino Acid Metabolism

Abstract

Mitochondria are central organelles that coordinate a vast array of metabolic and biologic functions important for cellular health. Amino acids are intricately linked to the bioenergetic, biosynthetic, and homeostatic function of the mitochondrion and require specific transporters to facilitate their import, export, and exchange across the inner mitochondrial membrane. Here we review key cellular metabolic outputs of eukaryotic mitochondrial amino acid metabolism and discuss both known and unknown transporters involved. Furthermore, we discuss how utilization of compartmentalized amino acid metabolism functions in disease and physiological contexts. We examine how improved methods to study mitochondrial metabolism, define organelle metabolite composition, and visualize cellular gradients allow for a more comprehensive understanding of how transporters facilitate compartmentalized metabolism.

Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias

“…Alanine is secreted by skeletal muscles and provides the carbon source for hepatic gluconeogenesis ( 168 , 169 ), yet limited information is available about the role of alanine metabolism in myeloid leukemias. Nevertheless, evidence supports that alanine provides a source of α-ketoglutarate for pancreatic and breast cancers that can be used to fuel the TCA cycle ( 170 , 171 ) or remodel the extracellular matrix for metastasis ( 172 ).…”

Bayesian Inference for Integrating Yarrowia lipolytica Multiomics Datasets with Metabolic Modeling

“…MLTHFtm is a transport reaction of 5,10-methylenetetrahydrofolate from the cytosol to the mitochondria by diffusion. In vivo, there is limited exchange between the cytoplasmic and mitochondrial pools of tetrahydrofolate (THF) and are instead linked by the transport of 1-carbon donors such as serine, glycine, and formate. − The model, therefore, does not represent the transport of 5,10-methylenetetrahydrofolate correctly, as it includes a secondary diffusion mechanism that is not observed to occur readily in nature. We will revisit this pathway using thermodynamics predicted based on the quantum mechanical modeling to make informed corrections before expanding the method to the genome scale.…”

Sex Differences in Molecular Mechanisms of Cardiovascular Aging

“…This figure shows evidence linking sex-differences to aging-mechanisms. protein metabolism (Hewton et al, 2021), regulation of apoptosis (Abate et al, 2020), maintenance of calcium concentration in the mitochondrial matrix (Finkel et al, 2015), and others. Aging impacts mitochondrial function, favoring damage to mitochondrial DNA (mtDNA).…”

“…The major function of mitochondria is to provide energy metabolism through the production of adenosine triphosphate (ATP), by oxidative phosphorylation ( Payne and Chinnery, 2015 ). In addition, mitochondria are involved in other cellular processes, including the formation of reactive species ( Abate et al, 2020 ), β-oxidation of fatty acids ( Houten et al, 2016 ), protein metabolism ( Hewton et al, 2021 ), regulation of apoptosis ( Abate et al, 2020 ), maintenance of calcium concentration in the mitochondrial matrix ( Finkel et al, 2015 ), and others. Aging impacts mitochondrial function, favoring damage to mitochondrial DNA (mtDNA).…”