Strategies for Improved Docosahexaenoic Acid Synthesis in Microalgae

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is essential for optimal brain growth and development. Fish oil is the main dietary source of DHA. However, off-flavors and contamination with persistent organic pollutants are the main issues when DHA is sourced ethically from deep-sea fishes. Microalgae offer a sustainable, viable option for DHA production. However, optimization of the DHA yield using low-cost materials helps in reducing the fermentation cost. In this systematic review, we cover recent progress on enhanced DHA production during the last ten years, 2015-2025. We discuss how mutagenomics, genetic engineering, and numerous growth supplementations help in enhanced DHA production. ARTP mutagenesis significantly improves DHA yield up to 41.4 g/L. While overexpression/co-overexpression/manipulating selected genes linked to the central carbohydrate metabolism, lipid metabolism showed DHA yield up to 51.5 g/L. Furthermore, sustainable, low-cost carbon and nitrogen sources of fermentation media enhanced microalgal biomass and DHA yield. DHA yield was 20.7 g/L using maize starch hydrolysate as a carbon source and soybean meal hydrolysate as a nitrogen source. In addition, cane molasses as a nitrogen source along with overexpressed sucrose dehydrogenase in an adaptive laboratory evolution (ALE) optimized microalgal strain displayed a 162.86% increase in DHA yield (25.26 g/L). Differentially expressed genes (DEGs) revealed from transcriptomics are aligned with the metabolomics profile of DHA-producing microalgae. Enzymes linked to the central carbohydrate metabolism, fatty acid synthase (FAS), and polyketide synthase (PKS) pathways were upregulated along with high cellular demands of NADPH and acetyl-CoA. We believe this review may be useful for further advancement of high-yield DHA-producing microalgae.