Mitochondrial dynamics and metabolism in induced pluripotency

Prieto, Javier; Ponsoda, Xavier; Belmonte, Juan Carlos Izpisúa; Torres, Josema

doi:10.1016/j.exger.2020.110870

Cited by 15 publications

(22 citation statements)

References 338 publications

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“…Overall, our work showing the early events driving the metabolic rewiring during cell reprogramming by c-MYC reinforce the existent parallels between cell reprogramming and tumorigenesis [4,55]. Furthermore, and similar to the observed epigenetic conversion during cell reprogramming [75], our data also suggest that an analogous passive process may take place during lipid remodelling.…”

Section: Discussionsupporting

confidence: 84%

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

Prieto

García-Cañaveras

León

et al. 2021

Stem Cell Rev and Rep

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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.

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Section: Discussionsupporting

confidence: 84%

“…It is known that c-MYC favours the biosynthesis of nucleic acids and lipids in cancer and somatic cells [4].…”

Section: Introductionmentioning

confidence: 99%

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

Prieto

García-Cañaveras

León

et al. 2021

Stem Cell Rev and Rep

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“…Cellular reprogramming to pluripotency and subsequent differentiation of induced pluripotent stem cells (iPSCs) are accompanied by a rewiring of mitochondrial respiration, mitochondrial network dynamics, and TCA cycle function. Such profound metabolic reprogramming impacts chromatin reorganization and reshapes the epigenome configuration to influence gene expression and change cellular identities [84][85][86][87]. Metformin imposes a metabolic shift away from the metabolic features that fuel pluripotency, thereby endowing fully differentiated somatic cells with a metabolic infrastructure that is protected against epigenetic reprogramming [88].…”

Section: Metformin: Countering the Erosion Of The Epigenetic Landscapementioning

confidence: 99%

Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity

Menendez

2020

Biomolecules

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The biguanide metformin is the first drug to be tested as a gerotherapeutic in the clinical trial TAME (Targeting Aging with Metformin). The current consensus is that metformin exerts indirect pleiotropy on core metabolic hallmarks of aging, such as the insulin/insulin-like growth factor 1 and AMP-activated protein kinase/mammalian Target Of Rapamycin signaling pathways, downstream of its primary inhibitory effect on mitochondrial respiratory complex I. Alternatively, but not mutually exclusive, metformin can exert regulatory effects on components of the biologic machinery of aging itself such as chromatin-modifying enzymes. An integrative metabolo-epigenetic outlook supports a new model whereby metformin operates as a guardian of cell identity, capable of retarding cellular aging by preventing the loss of the information-theoretic nature of the epigenome. The ultimate anti-aging mechanism of metformin might involve the global preservation of the epigenome architecture, thereby ensuring cell fate commitment and phenotypic outcomes despite the challenging effects of aging noise. Metformin might therefore inspire the development of new gerotherapeutics capable of preserving the epigenome architecture for cell identity. Such gerotherapeutics should replicate the ability of metformin to halt the erosion of the epigenetic landscape, mitigate the loss of cell fate commitment, delay stochastic/environmental DNA methylation drifts, and alleviate cellular senescence. Yet, it remains a challenge to confirm if regulatory changes in higher-order genomic organizers can connect the capacity of metformin to dynamically regulate the three-dimensional nature of epigenetic landscapes with the 4th dimension, the aging time.

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“…Indeed, the metabolism of PSCs and somatic cells is vastly different. PSCs are characterized by glycolytic metabolism linked to the high levels of energy needed to sustain rapid cell proliferation; conversely, differentiated cell metabolism is more flexible, where energy is formed by glycolysis and oxidative phosphorylation [ 100 , 101 ]. Moreover, PSCs showed lower levels of mitochondrial metabolism, marked by a reduced mitochondrion content and maturity.…”

Section: Ipscsmentioning

confidence: 99%

“…Moreover, PSCs showed lower levels of mitochondrial metabolism, marked by a reduced mitochondrion content and maturity. In particular, ESC mitochondria are globular with fewer cristae and contain matrices with low electron density [ 100 , 101 , 102 ]. Thus, when somatic cells enter in the reprogramming process, together with epigenetic and transcriptional reorganization, they undergo a remodeling of metabolic processes, shifting from highly oxidative respiratory metabolism to a glycolytic state.…”

Section: Ipscsmentioning

confidence: 99%

“Betwixt Mine Eye and Heart a League Is Took”: The Progress of Induced Pluripotent Stem-Cell-Based Models of Dystrophin-Associated Cardiomyopathy

Rovina

Castiglioni

Niro

et al. 2020

IJMS

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The ultimate goal of precision disease modeling is to artificially recreate the disease of affected people in a highly controllable and adaptable external environment. This field has rapidly advanced which is evident from the application of patient-specific pluripotent stem-cell-derived precision therapies in numerous clinical trials aimed at a diverse set of diseases such as macular degeneration, heart disease, spinal cord injury, graft-versus-host disease, and muscular dystrophy. Despite the existence of semi-adequate treatments for tempering skeletal muscle degeneration in dystrophic patients, nonischemic cardiomyopathy remains one of the primary causes of death. Therefore, cardiovascular cells derived from muscular dystrophy patients’ induced pluripotent stem cells are well suited to mimic dystrophin-associated cardiomyopathy and hold great promise for the development of future fully effective therapies. The purpose of this article is to convey the realities of employing precision disease models of dystrophin-associated cardiomyopathy. This is achieved by discussing, as suggested in the title echoing William Shakespeare’s words, the settlements (or “leagues”) made by researchers to manage the constraints (“betwixt mine eye and heart”) distancing them from achieving a perfect precision disease model.

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Mitochondrial dynamics and metabolism in induced pluripotency

Cited by 15 publications

References 338 publications

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

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

Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity

“Betwixt Mine Eye and Heart a League Is Took”: The Progress of Induced Pluripotent Stem-Cell-Based Models of Dystrophin-Associated Cardiomyopathy

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