Dysfunctional mitochondrial fission impairs cell reprogramming

Abstract

We have recently shown that mitochondrial fission is induced early in reprogramming in a Drp1-dependent manner; however, the identity of the factors controlling Drp1 recruitment to mitochondria was unexplored. To investigate this, we used a panel of RNAi targeting factors involved in the regulation of mitochondrial dynamics and we observed that MiD51, Gdap1 and, to a lesser extent, Mff were found to play key roles in this process. Cells derived from Gdap1-null mice were used to further explore the role of this factor in cell reprogramming. Microarray data revealed a prominent down-regulation of cell cycle pathways in Gdap1-null cells early in reprogramming and cell cycle profiling uncovered a G2/M growth arrest in Gdap1-null cells undergoing reprogramming. High-Content analysis showed that this growth arrest was DNA damage-independent. We propose that lack of efficient mitochondrial fission impairs cell reprogramming by interfering with cell cycle progression in a DNA damage-independent manner.

Mitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells

“…GDAP1 knockout MEFs form only 25% of the number of alkaline-phosphatase-positive colonies upon reprogramming when compared to control MEFs. Interestingly, a G2/M block seems to occur in GDAP1 -null cells (Prieto et al, 2016a), similar to that found during DRP1 inhibition (Qian et al, 2012). …”

“…During MEF reprogramming, mitochondrial fission appears to depend primarily on DRP1, MID51 and GDAP1 (Prieto et al, 2016a). MID51 is one of several mitochondrial outer membrane receptors for DRP1.…”

Targeted OMA1 therapies for cancer

“…[139][140][141] Changes in the dynamic mitochondrial network can also influence the identity, self-renewal capacity and commitment of stem cells, which reinforces the functional connection between morphology and metabolism, and which likely has implications for cancer (stem) cells as well. [142][143][144][145] Similar changes in the mitochondrial morphology have been observed also in T lymphocytes upon activation. Memory T cells on the other hand are quiescent, depend on oxidative phosphorylation, and hence showed a more fused morphology.…”

“…Interestingly, cancer cells and stem cells share the same energy metabolism and hence share a similar mitochondrial morphology . Changes in the dynamic mitochondrial network can also influence the identity, self‐renewal capacity and commitment of stem cells, which reinforces the functional connection between morphology and metabolism, and which likely has implications for cancer (stem) cells as well . Similar changes in the mitochondrial morphology have been observed also in T lymphocytes upon activation.…”

Fission for reprogramming

“…The activation of mitochondrial fission by phosphorylated Drp1 may precede the metabolic switch required for iPSC generation. In this issue of Cell Cycle, Prieto et al 4 provide additional data on the functional contribution of mitochondrial fission proteins to cellular reprogramming. The authors document that loss-of-function of proteins involved in this mitochondrial process such as GDAP1 or MiD51, reduced the OSKM-driven mitochondrial fragmentation characteristic of the early steps of reprogramming.…”