Mitochondrial Carriers and Substrates Transport Network: A Lesson from Saccharomyces cerevisiae

Abstract

The yeast Saccharomyces cerevisiae is one of the most widely used model organisms for investigating various aspects of basic cellular functions that are conserved in human cells. This organism, as well as human cells, can modulate its metabolism in response to specific growth conditions, different environmental changes, and nutrient depletion. This adaptation results in a metabolic reprogramming of specific metabolic pathways. Mitochondrial carriers play a fundamental role in cellular metabolism, connecting mitochondrial with cytosolic reactions. By transporting substrates across the inner membrane of mitochondria, they contribute to many processes that are central to cellular function. The genome of Saccharomyces cerevisiae encodes 35 members of the mitochondrial carrier family, most of which have been functionally characterized. The aim of this review is to describe the role of the so far identified yeast mitochondrial carriers in cell metabolism, attempting to show the functional connections between substrates transport and specific metabolic pathways, such as oxidative phosphorylation, lipid metabolism, gluconeogenesis, and amino acids synthesis. Analysis of the literature reveals that these proteins transport substrates involved in the same metabolic pathway with a high degree of flexibility and coordination. The understanding of the role of mitochondrial carriers in yeast biology and metabolism could be useful for clarifying unexplored aspects related to the mitochondrial carrier network. Such knowledge will hopefully help in obtaining more insight into the molecular basis of human diseases.

Compartmentalization engineering of yeasts to overcome precursor limitations and cytotoxicity in terpenoid production

“…Jia et al (2020) overexpressed mitochondria-related proteins including FIS1 for mitochondrial division, LSB3 for mitochondrial motility, MBA1 and AIM25 encoding other functional proteins to enhance the compartmentalized pathways, and the AIM25 gene boosted the sabinene titer to 154.9 mg/L. The understanding of mitochondrial physiology and metabolism could be useful to expand the applicability of mitochondrial engineering and realizing its full potential (Ferramosca and Zara, 2021).…”

Heterologous (Over) Expression of Human SoLute Carrier (SLC) in Yeast: A Well-Recognized Tool for Human Transporter Function/Structure Studies

“…One of the areas in which S. cerevisiae has proven to be an especially fruitful model is the area of mitochondrial research [ 154 ]. Indeed, the high similarity between yeast and human mitochondrial biogenesis and function renders S. cerevisiae an excellent model for studying human mitochondrial physiopathology [ 154 , 155 , 156 , 157 ]. Systematic approaches have been performed to optimize S. cerevisiae for recombinant membrane protein production, with the specific goal of understanding the molecular barriers to achieve high yields [ 158 ].…”

Ctp1 and Yhm2: Two Mitochondrial Citrate Transporters to Support Metabolic Flexibility of Saccharomyces cerevisiae

“…Therefore, this metabolic flexibility found in yeast depends on the specific substrates available during growth conditions. In this respect, mitochondrial carrier proteins play a key role because they transport a variety of substrates across the inner membrane of the organelles, thus connecting mitochondria with cytosolic reactions [10][11][12]. Among other 2 of 15 substrates, citrate is a key metabolic intermediate involved in several pathways and, therefore, the flux of this molecule between different cellular compartments is strictly regulated.…”

“…Extramitochondrial citrate generated by CIT2 is an intermediate of the glyoxylate pathway, which occurs in cytosol and peroxisomes, thus allowing yeast cells to make a net conversion of fatty acids to carbohydrates. Citrate can be therefore transported out and into mitochondria by using specific carrier proteins located in the mitochondrial inner membrane [11,15]. Therefore, an additional source of cytosolic citrate might be the export of mitochondrially produced citrate [15][16][17].…”