PUFAs such as ARA, EPA and DHA are important nutrients for human and animals, with essential physiological significance for infant brain development (Kris-Etherton et al., 2009), as well as the prevention of cancer and cardiovascular disease (Calder, 2018; Jia et al., 2022). Currently, various organizations around the world have given dietary advice on PUFAs. The Australia and New Zealand National Health and Medical Research Council recommends a dietary target of 430–610 mg/day of DHA/EPA/DPA (docosapentaenoic acid) for people aged 19–70. The International Society for the Study of Fatty Acids and Lipids recommends minimum daily intake of 500 mg of EPA + DHA for cardiovascular health (Kris-Etherton et al., 2009). Unfortunately, the dietary consumption of PUFAs in most populations does not reach the recommended minimum intake (Lenighan et al., 2019; O'Connor et al., 2021). With growing health awareness and improved quality of life, the global demand for PUFAs has also markedly increased. However, PUFAs are still generally obtained through extraction from animals and plants or chemical synthesis, which is unsustainable. Therefore, the search for a green and sustainable strategy for obtaining PUFAs is urgent.

Researchers have investigated various microorganisms as potential hosts for biosynthesis of PUFAs. As model microorganisms, E. coli and Saccharomyces cerevisiae are commonly used as chassis cells for the biosynthesis of diverse chemicals due to their powerful gene editing tools and abundance of biological parts. The PUFA biosynthesis pathway was recently reconstructed in E. coli, but the final yields of EPA and ARA reached only 4.1 mg/g and 8.3 mg/g, respectively (Thiyagarajan et al., 2021). In another study, DHA was biosynthesized in E. coli by heterologous expression of the Pfa gene cluster, and the DHA titer was improved to 16.8 mg/L by optimizing the addition of cerulenin and knocking out fabH gene (Giner-Robles et al., 2018). When egFAD2 gene was heterologous overexpressed in S. cerevisiae, the content of linoleic acid (LA) was only 12.3% of the total fatty acids (TFAs) (Sun et al., 2016). Apparently, the PUFA production capacity of E. coli and S. cerevisiae is far from the requirements of industrial production, indicating that even perfect gene editing cannot solve the mismatch of intrinsic strain performance. In nature, there exists a class of oleaginous microorganism with intracellular lipid content exceeding 20% (w/w) of DCW (Cai et al., 2022; Demir and Gundes, 2020), including well-known examples such as Y. lipolytica, M. alpina, and Thraustochytrids.

Generally, oleaginous microorganisms are divided into universal and specialized hosts according to the range of products that can be produced. Y. lipolytica is representative universal oleaginous microorganism, although its natural metabolism is capable of biosynthesizing only one PUFA (LA, C18:2). However, Y. lipolytica possesses advanced gene editing tools and a clear genetic background, so that it can be modified to biosynthesize multiple PUFAs, including ARA, EPA and DHA. Conversely, some oleaginous microorganisms are naturally able to efficiently biosynthesize specific PUFAs, such as Nannochloropsis for EPA, M. alpina for ARA, and Thraustochytrids for DHA. However, there are various in metabolic engineering and fermentation strategies due to the differences in strain performance and metabolic pathways. For example, Thraustochytrids utilize the anaerobic polyketide synthase pathway (PKS) to biosynthesize DHA, so regulating oxygen supply during fermentation is valuable strategy. Since Nannochloropsis is autotrophic microorganism, light has a remarkable effect on its growth and PUFA production. Therefore, summarizing the metabolic engineering and fermentation regulation strategies for different hosts is instructive for accelerating the industrial application of oleaginous microorganisms in the future.