Mitochondrial reprogramming in cell fate conversion and neural specification

Recent advances in stem cell technologies reveal the plasticity of the mammalian epigenome. We have previously demonstrated that mitochondria are also drastically reconfigured upon reprogramming of somatic cells to induced pluripotent stem cells (iPSCs), a process that is paralleled by a metabolic switch towards glycolysis. This glycolytic shift represents an early reprogramming event, preceding the expression of genes controlling pluripotency and self-renewal. Thus, metabolic transformation might control cell fate identity. Modulation of bioenergetics is particular important for the development of the nervous systems, which consumes almost half of the whole-organism basal metabolic rate. However, the regulatory role of mitochondria and energy metabolism in dictating neural commitment and orchestrating its epigenetic rewiring remains to be investigated.
In this project, we seek to dissect the potentially instructive role of bioenergetic restructuring for cell fate conversion and neural specification in particular. We will first focus on defined cellular states (fibroblasts, iPSCs, neural progenitors, neurons, and astrocytes) to map their mitochondrial/metabolic signature and the downstream effects on the epigenetic landscape. We will then analyze the mechanistic function of mitochondria and energy metabolism during reprogramming to iPSCs and upon glial and neuronal differentiation, by altering nutrient availability and by chemical and genetic manipulation of critical mitochondrial and metabolic regulators. Finally, we wish to integrate the obtained data to computationally build a metabolic map of cell identities. This will be coupled to mitochondrial-related high throughput assays to possibly identify enablers of metabolic-driven cellular conversions. Overall, these studies may lead to a better understanding of the importance of mitochondria and metabolism for brain development and for the control of cell fate plasticity and specification.

Figure 1: Metabolic restructuring during the induction of pluripotency and epigenetic crosstalk. Our previous works demonstrate that key metabolic players are differentially expressed in hESCs (red) compared to somatic fibroblasts (black) and that their reconfiguration takes place during reprogramming to iPSCs (orange). This metabolic restructuring might contribute to the rewiring of the epigenetic state (blue arrows) through histone and chromatin modifications.

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

Selected Publications


 

A Glycolytic Solution for Pluripotent Stem Cells.

Mlody B, Prigione A.

Cell Stem Cell. 2016 Oct;19(4):419-420. doi: 10.1016/j.stem.2016.09.005.

PMID:27716519

 

HIF1α modulates cell fate reprogramming through early glycolytic shift and upregulation of PDK1-3 and PKM2.

Prigione A, Rohwer N, Hoffmann S, Mlody B, Drews K, Bukowiecki R, Blümlein K, Wanker EE, Ralser M, Cramer T, Adjaye J.

Stem Cells. 2014 Feb;32(2):364-76. doi: 10.1002/stem.1552.

PMID:24123565

 

Mitochondrial function in pluripotent stem cells and cellular reprogramming.

Bukowiecki R, Adjaye J, Prigione A.

Gerontology. 2014;60(2):174-82. doi: 10.1159/000355050. Epub 2013 Nov 19. Review.

PMID:24281332

 

Human induced pluripotent stem cells harbor homoplasmic and heteroplasmic mitochondrial DNA mutations while maintaining human embryonic stem cell-like metabolic reprogramming.

Prigione A, Lichtner B, Kuhl H, Struys EA, Wamelink M, Lehrach H, Ralser M, Timmermann B, Adjaye J.

Stem Cells. 2011 Sep;29(9):1338-48. doi: 10.1002/stem.683.

PMID:21732474

 

Modulation of mitochondrial biogenesis and bioenergetic metabolism upon in vitro and in vivo differentiation of human ES and iPS cells.

Prigione A, Adjaye J.

Int J Dev Biol. 2010;54(11-12):1729-41. doi: 10.1387/ijdb.103198ap.

PMID:21305470

 

The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells.

Prigione A, Fauler B, Lurz R, Lehrach H, Adjaye J.

Stem Cells. 2010 Apr;28(4):721-33. doi: 10.1002/stem.404.

PMID: 20201066

Mitochondrial Medicine

Drawing by Helena P.

Mitochondria are membrane-bound organelles acting as the power plants of the cell, because they generate most of the cell's supply of adenosine triphosphate (ATP). They have their own genome and also divide independently of the cell in which they reside. In addition to their bioenergetic role, mitochondria are involved in a number of cellular functions, including calcium and redox homeostasis signaling, cellular differentiation, apoptosis, as well as in the maintenance of cell cycle and growth.

Mitochondrial impairment has been implicated in several human diseases, such as Leigh syndrome, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, and Autism. Mitochondrial disorders due to mutations in the mitochondrial DNA affect 1/5000 newborns. The nervous system is usually most affected, highlighting the dependence of neurons on mitochondrial functionality. No therapy or treatments currently exist, making mitochondrial diseases a significant burden for society.

iPSCs

iPSC-colony (red: NANOG)

Induced pluripotent stem cells (iPSCs) are generated by reprogramming adult somatic cells through forced expression of stem cell-specific transcription factors or related small molecules. iPSCs hold great promises in biomedical applications. Because they can propagate indefinitely, as well as give rise to every other cell type in the body, they may be employed for replacing defined tissues lost to damage or disease. Moreover, they can be used for model complex human disorders “in a dish”. Finally, iPSC derivatives may represent innovative cellular systems for the development of phenotype-driven drug discovery.