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Laying Bare the Molecular Mechanisms behind Mitochondrial Dynamics in Pluripotent Stem Cells

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Review of “A Non-apoptotic Function of MCL-1 in Promoting Pluripotency and Modulating Mitochondrial Dynamics in Stem Cells” from Stem Cell Reports by Stuart P. Atkinson

Studies have identified many of the dynamic changes that underpin both the emergence of the pluripotent state during somatic cell reprogramming and the loss of pluripotency during pluripotent stem cell (PSC) differentiation. While mitochondrial reorganization accompanies the reprogramming process [1], we understand little regarding the molecular mechanisms that control mitochondrial dynamics. 

Now, a study from the laboratory of Vivian Gama (Vanderbilt University, Nashville, TN, USA) describes a novel role for the myeloid cell leukemia 1 (MCL-1) protein, a cell death-associated BCL-2 family member involved in embryonic development [2], in regulating mitochondrial structure and pluripotency in PSCs, an unexpected new finding [3].

Initial studies by Rasmussen et al. established that PSC differentiation led to the downregulation of MCL-1 expression, while the induction of endogenous MCL-1 expression during the generation of induced pluripotent stem cells (iPSCs) correlated with the formation of a PSC-like fragmented mitochondrial network [1]. MCL-1 inhibition or knockdown promoted the attainment of a more differentiated cell-like mitochondrial network, marked by the fusion and elongation of mitochondria, and a reduction in the expression of crucial pluripotency transcription factors (NANOG and OCT4) thereby establishing a link between MCL-1 and the maintenance of the pluripotent state.

Interestingly, MCL-1 localization studies then highlighted the presence of MCL-1 in the outer mitochondrial membrane like other BCL-2 family members, but, uniquely, also in the mitochondrial matrix in PSCs. The subsequent expression of a matrix-targeted form of MCL-1 delayed PSC differentiation, overall suggesting that MCL-1 may play an alternative role in the mitochondrial matrix in maintaining pluripotency. 

Finally, the authors sought to understand the molecular mechanisms behind the function of MCL-1 in PSCs, demonstrating that MCL-1 interacted with and stabilized DRP-1 and OPA1, two GTPases responsible for remodeling the mitochondrial network. Accordingly, the depletion of MCL-1 led to the loss of DRP-1 and OPA1 levels and activity.

Overall, this fascinating new study forges a non-apoptotic role for MCL-1 in regulating mitochondrial dynamics and maintaining the pluripotent state in PSCs via interactions with mitochondrial fission and fusion regulators.

To discover more regarding the link between mitochondrial dynamics and pluripotency, including the role of MCL-1 in tissue-resident stem cells [4] and the full delineation of the molecular mechanisms at play, stay tuned to the Stem Cells Portal.

References

  1. Prieto J, León M, Ponsoda X, et al., Early ERK1/2 activation promotes DRP1-dependent mitochondrial fission necessary for cell reprogramming. Nature Communications 2016;7:11124.
  2. Rinkenberger JL, Horning S, Klocke B, et al., Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes & Development 2000;14:23-27.
  3. Rasmussen ML, Kline LA, Park KP, et al., A Non-apoptotic Function of MCL-1 in Promoting Pluripotency and Modulating Mitochondrial Dynamics in Stem Cells. Stem Cell Reports 2018;10:684-692.
  4. Khacho M, Clark A, Svoboda Devon S, et al., Mitochondrial Dynamics Impacts Stem Cell Identity and Fate Decisions by Regulating a Nuclear Transcriptional Program. Cell Stem Cell;19:232-247.