Functional Properties of the Mitochondrial Carrier System

Abstract

The mitochondrial carrier system (MCS) transports small molecules between mitochondria and the cytoplasm. It is integral to the core mitochondrial function to regulate cellular chemistry by metabolism. The mammalian MCS comprises the transporters of the 53 member canonical SLC25A family and a lesser number of identified non-canonical transporters. The recent discovery and investigations of the mitochondrial pyruvate carrier (MPC) illustrate the diverse effects a single mitochondrial carrier may exert on cellular function. However, the transport selectivities of many carriers remain unknown, and most have not been functionally investigated in mammalian cells. The mechanisms coordinating their function as a unified system remain undefined. Increased accessibility to molecular-genetic and metabolomic technologies now greatly enables investigation of the MCS. Continued investigation of the MCS may reveal how mitochondria encode complex regulatory information within chemical thermodynamic gradients. This understanding may enable precision modulation of cellular chemistry to counteract the dysmetabolism inherent in disease.

Lactate is oxidized outside of the mitochondrial matrix in rodent brain

“…Recently, the mitochondrial metabolism of lactate in cultured cancer cell lines was investigated more directly, using 13 C-labeled lactate and high-resolution mass spectrometry (Chen et al 2016). The results support the notion of a mitochondrial L-lactate carrier (Taylor 2017) and matrix LDHB in lactate-supported lipogenesis in proliferating, immortalized cells (Chen et al 2016). Whether this observation translates to mitochondria in mature, differentiated tissues like skeletal muscle and brain has not, to our knowledge, been reported.…”

Mitochondrial network responses in oxidative physiology and disease

“…Importantly, many of the ABC transporters have unknown activities so that network connections cannot be projected. A larger number of SLC transporters are known, and central functions of the SLC25 family in mitochondrial metabolism have been described [42,43]. Surprisingly from the standpoint of mitochondrial transport physiology, they have common structural features, with six transmembrane α-helices and a 3-fold repeated signature, but differences in energy coupling through functions as uniporters, symporters and antiporters [44,45].…”

Longitudinal MRI findings in patient with SLC25A12 pathogenic variants inform disease progression and classification

“…AGC1 is primarily expressed in the heart, skeletal muscle, and central nervous system whereas AGC2, a paralog of AGC1, is primarily expressed in epithelial cells and the liver (Amoedo et al, ). As one of two primary exchangers within the malate‐aspartate shuttle (the other being 2‐oxoglutarate carrier), AGC1 is involved in the transfer of nicotinamide adenine dinucleotide (NADH)‐reducing equivalents from the cytosol to the mitochondria, a transfer essential to connect the glycolytic and oxidative phases of glucose catabolism (Amoedo et al, ; Greenhouse & Lehninger, ; Ramos et al, ; Taylor, ). Aspartate produced in the mitochondria and exported to the cytosol is crucial for cell growth, proliferation, and synaptic transmission (Alkan et al, ; Birsoy et al, ; Sullivan et al, ), and in the brain, neuronal aspartate is continuously acetylated to form N ‐acetylaspartate (NAA).…”