Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms
- University of Utah, United States
- Harvard University, United States
- University of California, Davis, United States
- Van Andel Institute, United States
- University of Colorado Boulder, United States
- University of Helsinki, Finland
Abstract
Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature of aging and mitochondrial diseases, and cells closely monitor membrane potential as an indicator of mitochondrial health. Given its central importance, it is logical that cells would modulate mitochondrial membrane potential in response to demand and environmental cues, but there has been little exploration of this question. We report that loss of the Sit4 protein phosphatase in yeast increases mitochondrial membrane potential, both through inducing the electron transport chain and the phosphate starvation response. Indeed, a similarly elevated mitochondrial membrane potential is also elicited simply by phosphate starvation or by abrogation of the Pho85-dependent phosphate sensing pathway. This enhanced membrane potential is primarily driven by an unexpected activity of the ADP/ATP carrier. We also demonstrate that this connection between phosphate limitation and enhancement of mitochondrial membrane potential is observed in primary and immortalized mammalian cells as well as in Drosophila. These data suggest that mitochondrial membrane potential is subject to environmental stimuli and intracellular signaling regulation and raise the possibility for therapeutic enhancement of mitochondrial function even in defective mitochondria.
Data availability
The mass spectrometry data have been deposited to the ProteomeXchange Consortium with the data set identifier PXD037405. RNA sequencing data have been deposited to the GEO Omnibus Repository with data set identifiers GSE151606, GSE212790, and GSE209726. Code for high-throughput dataset analysis is archived on GitHub at https://github.com/j-berg/ouyang_analysis_2022, and at Zenodo at https://doi.org/10.5281/zenodo.7212729.
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Sequencing of yeast mutants with or without phosphate depletionNCBI Gene Expression Omnibus, GSE212790.
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Sequencing of yeast mutantsNCBI Gene Expression Omnibus, GSE209726.
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MCT1 deletion in Saccharomyces cerevisiaeNCBI Gene Expression Omnibus, GSE151606.
Article and author information
Author details
Jonathan G Van Vranken
Funding
National Institutes of Health (1F32GM140525)
- Corey N Cunningham
National Institutes of Health (1T32DK11096601)
- Jordan A Berg
National Institutes of Health (1F99CA253744)
- Jordan A Berg
National Institutes of Health (1F30CA243440-01A1)
- Jacob M Winter
National Institutes of Health (1K99HL168312-01)
- Ahmad A Cluntun
National Institutes of Health (R01GM110755)
- Dennis R Winge
National Institutes of Health (R35GM131854)
- Jared Rutter
Damon Runyon Cancer Research Foundation (DRG-2359-19)
- Jonathan G Van Vranken
Howard Hughes Medical Institute
- Jared Rutter
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2024, Ouyang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms
eLife 13:e84282.
https://doi.org/10.7554/eLife.84282
Further reading
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- Cell Biology
- Medicine
Background:
It has been reported that loss of PCBP2 led to increased reactive oxygen species (ROS) production and accelerated cell aging. Knockdown of PCBP2 in HCT116 cells leads to significant downregulation of fibroblast growth factor 2 (FGF2). Here, we tried to elucidate the intrinsic factors and potential mechanisms of bone marrow mesenchymal stromal cells (BMSCs) aging from the interactions among PCBP2, ROS, and FGF2.
Methods:
Unlabeled quantitative proteomics were performed to show differentially expressed proteins in the replicative senescent human bone marrow mesenchymal stromal cells (RS-hBMSCs). ROS and FGF2 were detected in the loss-and-gain cell function experiments of PCBP2. The functional recovery experiments were performed to verify whether PCBP2 regulates cell function through ROS/FGF2-dependent ways.
Results:
PCBP2 expression was significantly lower in P10-hBMSCs. Knocking down the expression of PCBP2 inhibited the proliferation while accentuated the apoptosis and cell arrest of RS-hBMSCs. PCBP2 silence could increase the production of ROS. On the contrary, overexpression of PCBP2 increased the viability of both P3-hBMSCs and P10-hBMSCs significantly. Meanwhile, overexpression of PCBP2 led to significantly reduced expression of FGF2. Overexpression of FGF2 significantly offset the effect of PCBP2 overexpression in P10-hBMSCs, leading to decreased cell proliferation, increased apoptosis, and reduced G0/G1 phase ratio of the cells.
Conclusions:
This study initially elucidates that PCBP2 as an intrinsic aging factor regulates the replicative senescence of hBMSCs through the ROS-FGF2 signaling axis.
Funding:
This study was supported by the National Natural Science Foundation of China (82172474).
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- Cancer Biology
- Cell Biology
The most common primary malignancy of the liver, hepatocellular carcinoma (HCC), is a heterogeneous tumor entity with high metastatic potential and complex pathophysiology. Increasing evidence suggests that tissue mechanics plays a critical role in tumor onset and progression. Here, we show that plectin, a major cytoskeletal crosslinker protein, plays a crucial role in mechanical homeostasis and mechanosensitive oncogenic signaling that drives hepatocarcinogenesis. Our expression analyses revealed elevated plectin levels in liver tumors, which correlated with poor prognosis for HCC patients. Using autochthonous and orthotopic mouse models we demonstrated that genetic and pharmacological inactivation of plectin potently suppressed the initiation and growth of HCC. Moreover, plectin targeting potently inhibited the invasion potential of human HCC cells and reduced their metastatic outgrowth in the lung. Proteomic and phosphoproteomic profiling linked plectin-dependent disruption of cytoskeletal networks to attenuation of oncogenic FAK, MAPK/Erk, and PI3K/Akt signatures. Importantly, by combining cell line-based and murine HCC models, we show that plectin inhibitor plecstatin-1 (PST) is well-tolerated and potently inhibits HCC progression. In conclusion, our study demonstrates that plectin-controlled cytoarchitecture is a key determinant of HCC development and suggests that pharmacologically induced disruption of mechanical homeostasis may represent a new therapeutic strategy for HCC treatment.
