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Pgam5 released from damaged mitochondria induces mitochondrial biogenesis via Wnt signaling.

ABSTRACT: Mitochondrial abundance is dynamically regulated and was previously shown to be increased by Wnt/?-catenin signaling. Pgam5 is a mitochondrial phosphatase which is cleaved by the rhomboid protease presenilin-associated rhomboid-like protein (PARL) and released from membranes after mitochondrial stress. In this study, we show that Pgam5 interacts with the Wnt pathway component axin in the cytosol, blocks axin-mediated ?-catenin degradation, and increases ?-catenin levels and ?-catenin-dependent transcription. Pgam5 stabilized ?-catenin by inducing its dephosphorylation in an axin-dependent manner. Mitochondrial stress triggered by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) treatment led to cytosolic release of endogenous Pgam5 and subsequent dephosphorylation of ?-catenin, which was strongly diminished in Pgam5 and PARL knockout cells. Similarly, hypoxic stress generated cytosolic Pgam5 and led to stabilization of ?-catenin, which was abolished by Pgam5 knockout. Cells stably expressing cytosolic Pgam5 exhibit elevated ?-catenin levels and increased mitochondrial numbers. Our study reveals a novel mechanism by which damaged mitochondria might induce replenishment of the mitochondrial pool by cell-intrinsic activation of Wnt signaling via the Pgam5-?-catenin axis.

SUBMITTER: Bernkopf DB

PROVIDER: S-EPMC5881504 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Pgam5 released from damaged mitochondria induces mitochondrial biogenesis via Wnt signaling.

Bernkopf Dominic B DB Jalal Kowcee K Brückner Martina M Knaup Karl X KX Gentzel Marc M Schambony Alexandra A Behrens Jürgen J

The Journal of cell biology 20180208 4

Mitochondrial abundance is dynamically regulated and was previously shown to be increased by Wnt/β-catenin signaling. Pgam5 is a mitochondrial phosphatase which is cleaved by the rhomboid protease presenilin-associated rhomboid-like protein (PARL) and released from membranes after mitochondrial stress. In this study, we show that Pgam5 interacts with the Wnt pathway component axin in the cytosol, blocks axin-mediated β-catenin degradation, and increases β-catenin levels and β-catenin-dependent t ...[more]

PMID: 29438981

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Project description:Mesenchymal stem cells (MSCs) protect tissues against cell death induced by ischemia/reperfusion insults. This therapeutic effect seems to be controlled by physiological cues released by the local microenvironment following injury. Recent lines of evidence indicate that MSC can communicate with their microenvironment through bidirectional exchanges of mitochondria. In particular, in vitro and in vivo studies report that MSCs rescue injured cells through delivery of their own mitochondria. However, the role of mitochondria conveyed from somatic cells to MSC remains unknown. By using a co-culture system consisting of MSC and distressed somatic cells such as cardiomyocytes or endothelial cells, we showed that mitochondria from suffering cells acted as danger-signaling organelles that triggered the anti-apoptotic function of MSC. We demonstrated that foreign somatic-derived mitochondria were engulfed and degraded by MSC, leading to induction of the cytoprotective enzyme heme oxygenase-1 (HO-1) and stimulation of mitochondrial biogenesis. As a result, the capacity of MSC to donate their mitochondria to injured cells to combat oxidative stress injury was enhanced. We found that similar mechanisms - activation of autophagy, HO-1 and mitochondrial biogenesis - occurred after exposure of MSC to exogenous mitochondria isolated from somatic cells, strengthening the idea that somatic mitochondria alert MSC of a danger situation and subsequently promote an adaptive reparative response. In addition, the cascade of events triggered by the transfer of somatic mitochondria into MSC was recapitulated in a model of myocardial infarction in vivo. Specifically, MSC engrafted into infarcted hearts of mice reduced damage, upregulated HO-1 and increased mitochondrial biogenesis, while inhibition of mitophagy or HO-1 failed to protect against cardiac apoptosis. In conclusion, our study reveals a new facet about the role of mitochondria released from dying cells as a key environmental cue that controls the cytoprotective function of MSC and opens novel avenues to improve the effectiveness of MSC-based therapies.

Dataset Information

Pgam5 released from damaged mitochondria induces mitochondrial biogenesis via Wnt signaling.

Publications

Pgam5 released from damaged mitochondria induces mitochondrial biogenesis via Wnt signaling.

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