Investigating Mitochondrial Rejuvenation During Cellular Reprogramming and Embryonic Development

The changes involved in producing induced pluripotent stem cells from ordinary somatic cells, such as those from a skin sample, are accompanied by mitochondrial rejuvenation, a clearance of mitochondrial damage associated with aging. This also occurs in the earliest stages of embryonic development, turning old parental cells into young child cells. It is not beyond the bounds of the possible to suggest that perhaps just this mitochondrial part of the transformation could be split off and used as the basis for a therapy - though other approaches to mitochondrial repair are far closer to realization. Also, it may well be that mitochondria are so vital to cellular function that it is impossible to safely induce such radical changes in adult tissues given the way in which cells are presently structured. As usual, the only way to find out is to dig deeper into what is going on under the hood, as researchers are doing here. The original research release is in PDF format only, unfortunately, but it provides a better explanation than any of the other available resources:

A new study suggests that old mitochondria - the oxygen-consuming metabolic engines in cells - are roadblocks to cellular rejuvenation. By tuning up a gene called Tcl1, which is highly abundant in eggs, researchers were able to suppress old mitochondria to enhance a process known as somatic reprogramming, which turn adult cells into embryonic-like stem cells. Researchers found that Tcl1 does its job by suppressing mitochondrial polynucleotide phosphorylase (PnPase), thereby inhibiting mitochondrial growth and metabolism.

Stem cell researchers had known that egg (or oocyte) cytoplasm contains some special unknown factors that can reprogramme adult cells into embryonic-like stem cells, either during egg-sperm fertilisation or during artificial cloning procedures. While researchers had invented a technology called induced pluripotent stem cell (iPSC) reprogramming to replace the ethically controversial oocyte-based reprogramming technique, oocyte-based reprogramming was still deemed superior in complete cellular reprogramming efficiency. To address this shortfall, researchers combined oocyte factors with the iPSC reprogramming system. Their bioinformatics-driven screening efforts1 led to two genes: Tcl1 and its cousin Tcl1b1. After a deeper investigation, the team found that the Tcl1 genes were acting via the mitochondrial enzyme, PnPase. "We were quite surprised, because nobody would have thought that the key to the oocyte's reprogramming powers would be a mitochondrial enzyme. The stem cell field's conventional wisdom suggests that it should have been some other signalling genes instead."

Tcl1 is a cytoplasmic protein that binds to the mitochondrial enzyme PnPase. By locking PnPase in the cytoplasm, Tcl1 prevents PnPase from entering mitochondria, thereby suppressing its ability to promote mitochondrial growth and metabolism. Thus, an increase in Tcl1 suppresses old mitochondria's growth and metabolism in adult cells, to enhance the somatic reprogramming of adult cells into embryonic-like stem cells. These new insights could boost efficacy of the alternative, non-oocyte based iPSC techniques for stem cell banking, organ and tissue regeneration, as well as further our understanding of how cellular metabolism rejuvenates after egg-sperm fertilisation.



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