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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.

SUBMITTER: Prieto J

PROVIDER: S-EPMC5176137 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Dysfunctional mitochondrial fission impairs cell reprogramming.

Prieto Javier J León Marian M Ponsoda Xavier X García-García Francisco F Bort Roque R Serna Eva E Barneo-Muñoz Manuela M Palau Francesc F Dopazo Joaquín J López-García Carlos C Torres Josema J

Cell cycle (Georgetown, Tex.) 20161018 23

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 t ...[more]

PMID: 27753531

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Project description:The majority of transplanted kidneys are procured from deceased donors which all require exposure to cold storage (CS) for successful transplantation. Unfortunately, this CS leads to renal and mitochondrial damage but, specific mitochondrial targets affected by CS remain largely unknown. The goal of this study is to determine whether pathways involved with mitochondrial fusion or fission, are disrupted during renal CS.Male Lewis rat kidneys were exposed to cold storage (CS) alone or cold storage combined with transplantation (CS/Tx). To compare effects induced by CS, kidney transplantation without CS exposure (autotransplantation; ATx) was also used. Mitochondrial function was assessed using high resolution respirometry. Expression of mitochondrial fusion and fission proteins were monitored using Western blot analysis.CS alone (no Tx) reduced respiratory complex I and II activities along with reduced expression of the primary mitochondrial fission protein, dynamin related protein (DRP1), induced loss of the long form of Optic Atrophy Protein (OPA1), and altered the mitochondrial protease, OMA1, which regulates OPA1 processing. CS followed by Tx (CS/Tx) reduced complex I, II, and III activities, and induced a profound loss of the long and short forms of OPA1, mitofusin 1 (MFN1), and mitofusin 2 (MFN2) which all control mitochondrial fusion. In addition, expression of DRP1, along with its primary receptor protein, mitochondrial fission factor (MFF), were also reduced after CS/Tx. Interestingly, CS/Tx lead to aberrant higher molecular weight OMA1 aggregate expression.Our results suggest that CS appears to involve activation of the OMA1, which could be a key player in proteolysis of the fusion and fission protein machinery following transplantation. These findings raise the possibility that impaired mitochondrial fission and fusion may be unrecognized contributors to CS induced mitochondrial injury and compromised renal graft function after transplantation.

Dataset Information

Dysfunctional mitochondrial fission impairs cell reprogramming.

Publications

Dysfunctional mitochondrial fission impairs cell reprogramming.

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