Fatty acid synthesis is critical for stem cell pluripotency via promoting mitochondrial fission

Abstract

Pluripotent stem cells are known to display distinct metabolic phenotypes than their somatic counterparts. While accumulating studies are focused on the roles of glucose and amino acid metabolism in facilitating pluripotency, little is known regarding the role of lipid metabolism in regulation of stem cell activities. Here, we show that fatty acid (FA) synthesis activation is critical for stem cell pluripotency. Our initial observations demonstrated enhanced lipogenesis in pluripotent cells and during cellular reprogramming. Further analysis indicated that de novo FA synthesis controls cellular reprogramming and embryonic stem cell pluripotency through mitochondrial fission. Mechanistically, we found that de novo FA synthesis regulated by the lipogenic enzyme ACC1 leads to the enhanced mitochondrial fission via (i) consumption of AcCoA which affects acetylation‐mediated FIS1 ubiquitin–proteasome degradation and (ii) generation of lipid products that drive the mitochondrial dynamic equilibrium toward fission. Moreover, we demonstrated that the effect of Acc1 on cellular reprogramming via mitochondrial fission also exists in human iPSC induction. In summary, our study reveals a critical involvement of the FA synthesis pathway in promoting ESC pluripotency and iPSC formation via regulating mitochondrial fission.

Metabolism in pluripotency: Both driver and passenger?

“…Glutamine supports PSC survival and expansion by increasing antioxidant glutathione (4) and fueling mitochondrial energy metabolism (12)(13)(14). Glutaminolysis generates tricarboxylic acid (TCA) cycle substrates (12) and supports the mitochondrial inner membrane potential (Δ) required for PSC survival (15).…”

“…Lipid production also supports somatic cell reprogramming to pluripotency (18,19). Carbons for lipid building are siphoned from glycolysis and glutaminolysis biochemical pathways (12,14). Indeed, lipid anabolism promotes PSC identity, notably by regulating mitochondrial dynamics (see next section).…”

“…PSCs show punctate mitochondria with immature inner membrane cristae and evidence of reduced functionality with low OXPHOS (2,4,5) and ROS production (14,26). A granular mitochondrial morphology contrasts with elongated interlacing mitochondrial networks in somatic cells and helps to sustain CPTF expression and prevent expression of differentiation genes (27).…”

“…A granular mitochondrial morphology supports fatty acid (FA) biosynthesis and promotes glycolytic gene expression (14). Studies show that mitochondrial fission with an immature ultrastructure, rather than function of respiratory chain complexes, supports a glycolytic preference (2,4,5).…”

“…Equilibrium toward mitochondrial fission is driven by lipogenic enzyme (ACC1) inhibition of mitochondrial fission factor (FIS1), ubiquitin-proteasome degradation, and the lipid generation (14). Mitochondrial dynamics is further supported by reduction of MFN1/2, and an increase of the mitochondrial A-kinase anchoring protein RAB32 involved in mitochondrial fission synchronization (26,47).…”