SLC25A1, in the inner mitochondrial membrane, mediates the exchange of mitochondrial citrate for cytosolic malate (Gnoni et al., 2009; reviewed in Zara et al., 2022). Mutations in SLC25A1 can cause neonatal-onset encephalopathy (D2L2AD, MIM:615182; Edvarson et al., 2013; Majd et al., 2018; reviewed by Zara et al., 2023) and a form of congenital myasthenic syndrome (CMS23, MIM:618197; Chaouch et al., 2014). SLC25A1 citrate export together with acetyl-CoA production by ACLY are sometimes referred to as the citrate-malate shuttle (for a review see Guo et al., 2023).

A variety of models assign phosphoenolpyruvate (PEP) generated in the mitochondrial matrix by PCK2 (Phosphoenolpyruvate carboxykinase (GTP), mitochondrial) a role in the regulation of gluconeogenesis and its integration with other aspects of metabolism (e.g., Bluemel et al. 2021; Merrins et al. 2022; Soling et al. 1973; Yu et al. 2021). An attractive recent suggestion is that this process may specifically play a key role in regulating insulin secretion by pancreatic beta cells in response to changing blood glucose levels (Merrins et al. 2022).

Exchange of citrate for PEP across a membrane has been demonstrated in several model systems (Kleineke et al. 1973; Robinson 1971; Shug & Shrago 1973; Sul et al. 1976; Stipani et al, 1980) but the direction in which it proceeds under physiological conditions and the identity of the protein or proteins that enable this exchange remain unclear, although the citrate transporter SLC25A1 has been identified as a candidate.

Here, this hypothetical reaction is annotated as the exchange of mitochondrial PEP for an unspecified cytosolic anion, A-, possibly mediated by SLC25A1.

Mitochondrial glutamate carriers 1 and 2 (SLC25A22, GC1, and SLC25A18, GC2) belong to the mitochondrial carrier family of transport proteins that shuttle substrates, metabolites, and cofactors through the mitochondrial membrane, connecting the cytosol to the mitochondrial matrix. Glutamate (Glu) can be co-transported with H+ via SLC25A18 and SLC25A22, located on the inner mitochondrial membrane (Fiermonte et al., 2002). Defects in SLC25A22 can cause early infantile epileptic encephalopathy 3 (EIEE3; MIM:609304), a severe neonatal epilepsy characterized by very early onset, erratic and fragmentary myoclonus. With no treatment available, children with EIEE3 die within 1 or 2 years of birth or survive in a vegetative state (Molinari et al., 2005; reviewed in Spoto et al., 2021).

The SLC25A11 transport protein in the inner mitochondrial membrane mediates the reversible exchange of mitochondrial alpha-ketoglutarate (2OG, 2-oxoglutarate) and cytosolic malate (MAL) (Booty et al., 2015; Kabe et al. 2006). Kinetic details were also inferred from studies of rat mitochondria under conditions in which only the one transport protein appears to be active (Sluse et al. 1973). The dimeric state of the transport protein is inferred from studies of its bovine homologue (Bisaccia et al. 1996). Mutations in SLC25A11 can cause adult-onset development of paragangliomas (PGL6, MIM:618464; Buffet et al., 2018).

Calcium-binding mitochondrial carrier proteins SLC25A12 (Aralar, AGC1) and SLC25A13 (Citrin, Aralar2, AGC2), located in the inner mitochondrial membrane, mediate the exchange of cytosolic aspartate and mitochondrial glutamate (Palmieri et al., 2001; González-Moreno et al., 2023). The exchange is physiologically irreversible because of the potential across the inner mitochondrial membrane (positive outside, negative inside). In the body, SLC25A12 is found mainly in the heart, skeletal muscle, and brain, while SCL25A13 is widely expressed but most abundant in the liver (del Arco et al., 2000; Palmieri et al., 2001). Mutations in SLC25A12 can cause a form of early-onset epileptic encephalopathy (DEE39, MIM:612949; Wibom et al., 2009; reviewed in Pardo et al., 2022). Defects in SLC25A13 are associated with type II citrullinemia, characterized by a liver-specific deficiency of the urea cycle enzyme argininosuccinate synthase (Kobayashi et al., 1999, Saheki et al., 2002; González-Moreno et al., 2023; reviewed in Hayasaka, 2021)

SLC25A10, the mitochondrial dicarboxylate carrier protein in the inner mitochondrial membrane, mediates the reversible exchange of mitochondrial malate for cytosolic phosphate (Fiermonte et al. 1999). Mutations in the human SLC25A10 gene disrupt malate transport and are associated with severe clinical phenotypes (Punzi et al. 2018).

Tricarboxylate transport protein, mitochondrial