Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5

Abstract

The small molecule citrate is a key molecule that is synthesized de novo and involved in diverse biochemical pathways influencing cell metabolism and function. Citrate is highly abundant in the circulation, and cells take up extracellular citrate via the sodium-dependent plasma membrane transporter NaCT encoded by the SLC13A5 gene. Citrate is critical to maintaining metabolic homeostasis and impaired NaCT activity is implicated in metabolic disorders. Though citrate is one of the best known and most studied metabolites in humans, little is known about the consequences of altered citrate uptake and metabolism. Here, we review recent findings on SLC13A5, NaCT, and citrate metabolism and discuss the effects on metabolic homeostasis and SLC13A5-dependent phenotypes. We discuss the “multiple-hit theory” and how stress factors induce metabolic reprogramming that may synergize with impaired NaCT activity to alter cell fate and function. Furthermore, we underline how citrate metabolism and compartmentalization can be quantified by combining mass spectrometry and tracing approaches. We also discuss species-specific differences and potential therapeutic implications of SLC13A5 and NaCT. Understanding the synergistic impact of multiple stress factors on citrate metabolism may help to decipher the disease mechanisms associated with SLC13A5 citrate transport disorders.

Epileptic phenotypes inslc13a5loss-of-function zebrafish are rescued by blocking NMDA receptor signaling

“…In contrast, maximum respiratory capacity and reserve capacity were upregulated by 28.2% and 351.2%, respectively (5a -/-;5b -/-), whereas proton leaks were unchanged (Fig. S5A-C), consistent with other reports whereby the loss of citrate uptake by cells due to SLC13A5 mutations causes changes in cellular metabolism (42)(43)(44)(45).…”

“…We speculate that this increased apoptosis is a consequence of seizure-like events in the mutant brain, since other animal model and patient data show that epileptic seizures cause neuronal death via activation of apoptosis or autophagy signaling pathways (34, 53-55). It is also possible that a block in citrate transport causes a loss of intracellular citrate, a crucial metabolite for energy production, and thus alters neuronal metabolic health (43). Our zebrafish slc13a5 mutants exhibited compromised neurometabolism, consistent with a metabolic phenotype.…”

Novel Approaches to Studying SLC13A5 Disease

“…Interestingly, low glutamate levels in the cerebrospinal fluid (CSF) of SLC13A5 patients [39] might impact the balance between excitatory and inhibitory neurotransmission, leading to epilepsy. Moreover, changes in acetyl-CoA levels can broadly affect neuronal function and GABA signaling [173]. Therefore, co-cultures of iPSC-derived neurons and astrocytes, or brain organoids, are valuable tools for investigating how SLC13A5 deficiency affects the glutamate-glutamine shuttle and to explore the NaCT's role in citrate metabolism, neurotransmission balance, and GABA synthesis.…”