¡Viva la mitochondria!: harnessing yeast mitochondria for chemical production

Duran, Lisset; López, José Montaño; Avalos, José L.

doi:10.1093/femsyr/foaa037

Cited by 18 publications

(13 citation statements)

References 114 publications

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“…As sites of the βoxidation of fatty acids, peroxisomes can supply ample acetyl-CoA (van der Klei and Veenhuis, 1997). Similarly, mitochondria have nearly 20-30 times higher acetyl-CoA content than the cytosol (Duran et al, 2020). As shown in Figure 2C, rational organelle compartmentalization can greatly improve the utilization efficiency of the acetyl-CoA pools in different organelles (Son et al, 2022a;Lu et al, 2022).…”

Section: Monoterpenoids and Sesquiterpenoidsmentioning

confidence: 89%

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

Chen

Xiao

Yao

et al. 2023

Front. Bioeng. Biotechnol.

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Metabolic engineering strategies for terpenoid production have mainly focused on bottlenecks in the supply of precursor molecules and cytotoxicity to terpenoids. In recent years, the strategies involving compartmentalization in eukaryotic cells has rapidly developed and have provided several advantages in the supply of precursors, cofactors and a suitable physiochemical environment for product storage. In this review, we provide a comprehensive analysis of organelle compartmentalization for terpenoid production, which can guide the rewiring of subcellular metabolism to make full use of precursors, reduce metabolite toxicity, as well as provide suitable storage capacity and environment. Additionally, the strategies that can enhance the efficiency of a relocated pathway by increasing the number and size of organelles, expanding the cell membrane and targeting metabolic pathways in several organelles are also discussed. Finally, the challenges and future perspectives of this approach for the terpenoid biosynthesis are also discussed.

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Section: Monoterpenoids and Sesquiterpenoidsmentioning

confidence: 89%

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

Chen

Xiao

Yao

et al. 2023

Front. Bioeng. Biotechnol.

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“…Unlike monolayers of LDs and peroxisomes, mitochondria are semi-autonomous organelles surrounded by two layers of membrane, with their inner membrane forming mutliple ridges, which can gradually release energy through respiration to meet the requirements of various cell activities. Because acetyl-CoA is an important precursor for terpenoid synthesis, mitochondria have a much higher acetyl-CoA content (nearly 20–30 times higher) than the cytoplasm, which increases the feasibility of mitochondrial compartmentalization for terpenoid synthesis [ 79 , 80 ]. However, IPP and DMAPP, which are synthesized from acetyl-CoA via the MVA pathway, are ATP analogs that are strong inhibitors of the mitochondrial respiratory chain.…”

Section: Compartmentalization Strategies For Effective Synthesis Of T...mentioning

confidence: 99%

Compartmentalization and transporter engineering strategies for terpenoid synthesis

Jin

Xia²,

Liu

et al. 2022

Microb Cell Fact

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Microbial cell factories for terpenoid synthesis form a less expensive and more environment-friendly approach than chemical synthesis and extraction, and are thus being regarded as mainstream research recently. Organelle compartmentalization for terpenoid synthesis has received much attention from researchers owing to the diverse physiochemical characteristics of organelles. In this review, we first systematically summarized various compartmentalization strategies utilized in terpenoid production, mainly plant terpenoids, which can provide catalytic reactions with sufficient intermediates and a suitable environment, while bypassing competing metabolic pathways. In addition, because of the limited storage capacity of cells, strategies used for the expansion of specific organelle membranes were discussed. Next, transporter engineering strategies to overcome the cytotoxic effects of terpenoid accumulation were analyzed. Finally, we discussed the future perspectives of compartmentalization and transporter engineering strategies, with the hope of providing theoretical guidance for designing and constructing cell factories for the purpose of terpenoid production.

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“…Most synthetic pathways are targeted to the cytosol due to its big volume, high coverage of metabolic enzymes and metabolites [ 3 , 4 ]. Recent studies have revealed that the yeast mitochondrion could be attractive to produce terpenoids, fumarate, ornithine, and branched-chain alcohols [ 5 – 7 ]. With the mevalonate pathway and sequential synthetic genes targeted into the mitochondria, researchers have greatly improved the titers of isoprene, patchoulol, valencene, amorphadiene, linalool and santalene [ 8 – 12 ].…”

Section: Introductionmentioning

confidence: 99%

Engineering yeast mitochondrial metabolism for 3-hydroxypropionate production

Zhang

Chen

et al. 2023

Biotechnol Biofuels

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Background With unique physiochemical environments in subcellular organelles, there has been growing interest in harnessing yeast organelles for bioproduct synthesis. Among these organelles, the yeast mitochondrion has been found to be an attractive compartment for production of terpenoids and branched-chain alcohols, which could be credited to the abundant supply of acetyl-CoA, ATP and cofactors. In this study we explored the mitochondrial potential for production of 3-hydroxypropionate (3-HP) and performed the cofactor engineering and flux control at the acetyl-CoA node to maximize 3-HP synthesis. Results Metabolic modeling suggested that the mitochondrion serves as a more suitable compartment for 3-HP synthesis via the malonyl-CoA pathway than the cytosol, due to the opportunity to obtain a higher maximum yield and a lower oxygen consumption. With the malonyl-CoA reductase (MCR) targeted into the mitochondria, the 3-HP production increased to 0.27 g/L compared with 0.09 g/L with MCR expressed in the cytosol. With enhanced expression of dissected MCR enzymes, the titer reached to 4.42 g/L, comparable to the highest titer achieved in the cytosol so far. Then, the mitochondrial NADPH supply was optimized by overexpressing POS5 and IDP1, which resulted in an increase in the 3-HP titer to 5.11 g/L. Furthermore, with induced expression of an ACC1 mutant in the mitochondria, the final 3-HP production reached 6.16 g/L in shake flask fermentations. The constructed strain was then evaluated in fed-batch fermentations, and produced 71.09 g/L 3-HP with a productivity of 0.71 g/L/h and a yield on glucose of 0.23 g/g. Conclusions In this study, the yeast mitochondrion is reported as an attractive compartment for 3-HP production. The final 3-HP titer of 71.09 g/L with a productivity of 0.71 g/L/h was achieved in fed-batch fermentations, representing the highest titer reported for Saccharomyces cerevisiae so far, that demonstrated the potential of recruiting the yeast mitochondria for further development of cell factories.

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¡Viva la mitochondria!: harnessing yeast mitochondria for chemical production

Cited by 18 publications

References 114 publications

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

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

Compartmentalization and transporter engineering strategies for terpenoid synthesis

Engineering yeast mitochondrial metabolism for 3-hydroxypropionate production

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