c-MYC Triggers Lipid Remodelling During Early Somatic Cell Reprogramming to Pluripotency

Abstract

Metabolic rewiring and mitochondrial dynamics remodelling are hallmarks of cell reprogramming, but the roles of the reprogramming factors in these changes are not fully understood. Here we show that c-MYC induces biosynthesis of fatty acids and increases the rate of pentose phosphate pathway. Time-course profiling of fatty acids and complex lipids during cell reprogramming using lipidomics revealed a profound remodelling of the lipid content, as well as the saturation and length of their acyl chains, in a c-MYC-dependent manner. Pluripotent cells displayed abundant cardiolipins and scarce phosphatidylcholines, with a prevalence of monounsaturated acyl chains. Cells undergoing cell reprogramming showed an increase in mitochondrial membrane potential that paralleled that of mitochondrial-specific cardiolipins. We conclude that c-MYC controls the rewiring of somatic cell metabolism early in cell reprogramming by orchestrating cell proliferation, synthesis of macromolecular components and lipid remodelling, all necessary processes for a successful phenotypic transition to pluripotency. Graphical Abstract c-MYC promotes anabolic metabolism, mitochondrial fitness and lipid remodelling early in cell reprogramming. A high rate of aerobic glycolysis is crucial to provide intermediaries for biosynthetic pathways. To ensure the availability of nucleotides, amino acids and lipids for cell proliferation, cells must provide with a constant flux of the elemental building blocks for macromolecule assembly and fulfil the anabolic demands to reach the critical cellular mass levels to satisfactorily undergo cell division. A high rate of aerobic glycolysis is induced by c-MYC, increasing the amounts of intracellular Glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), and glyceraldehyde-3-phosphate (GA3P), which can all enter pentose phosphate pathway (PPP) to produce Ribose-5-Phosphate (R5P) and NADPH, which are necessary for the biosynthesis of biomolecules such as proteins, nucleic acids, or lipids. C-MYC-dependent activation of glucose-6-phosphate dehydrogenase (G6PD) may play a critical role in the shunting of G6P to PPP and generation of NADPH. High glycolytic flux increases the amounts of dihydroxyacetone phosphate (DHAP), which is crucial for biosynthesis of phospholipids and triacylglycerols, and pyruvate (Pyr), which can be converted to citrate (Cit) in the mitochondria and enter the biosynthesis of fatty acids (FA). During cell reprogramming, c-MYC-dependent lipid remodelling leads to Polyunsaturated Fatty Acid (PUFA) downregulation and Monounsaturated Fatty Acid (MUFA) upregulation, which may play critical roles in cytoarchitectural remodelling of cell membrane or non-canonical autophagy, respectively. Cardiolipin (pink dots) rise early in cell reprogramming correlates with an increase in mitochondrial fitness, suggesting that c-MYC may restore proper levels of cardiolipins and antioxidant proteins, such as UCP2, to guarantee an optimal mitochondrial function while upholding ROS levels, reinforcing the idea of cell rejuvenation early in cell reprogramming.

LPLUNC1 reduces glycolysis in nasopharyngeal carcinoma cells through the PHB1‐p53/c‐Myc axis

“… 19 , 45 Our previous study has indicated that LPLUNC1 can upregulate PHB1 expression and enhance its stabilization by reducing its ubiquitination degradation to attenuate the NF‐kB signaling, 18 supporting the notion that PHB1 can affect multiple signal pathways to inhibit tumor cell proliferation. 19 , 24 , 29 , 41 In this study, we found that LPLUNC1 upregulated PHB1 protein expression and promoted phosphorylated PHB1 nuclear translocation by upregulating the expression of 14‐3‐3σ, an endoplasmic reticulum lipid raft protein. 34 , 46 Our data indicated that PHB1 Tyr259 phosphorylation was critical for its action in decreasing glycolysis and increasing OXPHOS‐related protein expression in NPC cells.…”

“… 28 In contrast, c‐Myc is highly expressed in a variety of tumors and can enhance glycolysis and activation of the PPP in different types of tumor cells. 18 , 29 Previous studies have shown that PHB1 can downregulate the expression of c‐Myc in tumor cells. 30 We hypothesize that LPLUNC1 may modulate p53 and c‐Myc expression by enhancing PHB1 to regulate glucose metabolism in NPC cells.…”

HSPB8 binding to c-Myc alleviates hypoxia/reoxygenation-induced trophoblast cell dysfunction

“…In addition, c-Myc has been reported to inhibit oxidative stress during ventricular remodeling of rats with myocardial infarction ( 54 ). c-Myc may restore appropriate levels of antioxidant proteins to ensure optimal mitochondrial function while maintaining ROS levels ( 55 ). Kfoury et al proposed that ROS levels are significantly increased in melanoma cells following knockdown of c-Myc expression, which promotes the induction of apoptosis of melanoma cells ( 56 ).…”

Metabolic control of induced pluripotency

“…After completing MET, cells increase their proliferation rate, suppressing proapoptotic and senescence factors, which are required for extensive epigenetic modification ( Marion et al, 2009a ; Hong et al, 2009 ; Utikal et al, 2009 ; Yunusova et al, 2017 ). MET also leads to the upregulation of genes involved in cell proliferation, metabolism, and cytoskeletal organization—c-Myc, MycN, KLF4, and Pdzk1 ( Prieto et al, 2021 ). At this stage, cells lack DNA methylation, and active histone modifications mediate the suppression of cell type-specific genes ( Polo et al, 2012 ).…”