In the realm of cellular biology, the mitochondrial unfolded protein response (UPR^mt) has long been recognized as a pivotal signaling pathway that communicates mitochondrial stress to the nucleus, orchestrating adaptive responses to preserve mitochondrial integrity. While studies in model organisms such as Caenorhabditis elegans have firmly established UPR^mt as a critical player in longevity and stress adaptation, its functional significance in mammalian development and cell fate decisions has remained a tantalizing mystery. A groundbreaking study recently published in Nature Metabolism now unveils a surprising and intricate role for UPR^mt in the regulation of cellular reprogramming and plasticity, with far-reaching implications for stem cell biology and cancer metastasis.
Investigators led by Ying et al. have discovered that the activation of UPR^mt is not merely a stress response but an active participant during the early stages of reprogramming somatic cells into pluripotent stem cells. Specifically, in mouse embryonic fibroblasts undergoing induced pluripotency reprogramming, a transient surge in UPR^mt activation coincides with a decrease in mitochondrial proteolytic activity, orchestrated by the oncogenic transcription factor c-Myc. This temporal modulation suggests that mitochondrial quality control and proteostasis are dynamically remodeled as cells transition toward pluripotency, challenging the long-held notion that mitochondrial stress responses are only invoked under pathological conditions.
More strikingly, the UPR^mt pathway imposes a blockade on the mesenchymal-to-epithelial transition (MET), a critical early event in cellular reprogramming characterized by the acquisition of epithelial traits necessary for the establishment of pluripotency. Central to this inhibitory mechanism is the transcription factor c-Jun, which is induced downstream of UPR^mt activation. Ying and colleagues elucidate that c-Jun acts as a molecular brake on MET by fine-tuning the metabolic and epigenetic landscape of reprogramming cells. This repressive effect on MET, mediated via c-Jun, underscores a novel mitochondria-to-nucleus communication axis that integrates mitochondrial stress signaling, metabolism, and chromatin remodeling.
Delving into the mechanistic underpinnings, the researchers show that c-Jun stimulates the expression of enzymes involved in acetyl-CoA metabolism, culminating in a reduction of intracellular acetyl-CoA levels. Because acetyl-CoA is a key substrate for histone acetylation, particularly H3K9 acetylation (H3K9Ac), its depletion leads to global changes in chromatin acetylation status. Notably, c-Jun-mediated decreases in H3K9Ac occupancy at promoters of MET-associated genes result in a repressive chromatin environment that hinders the transcriptional activation required for MET progression. This revelation places mitochondrial dynamics and metabolite availability at the forefront of epigenetic regulation during cell fate transitions.
The implications of this study extend beyond reprogramming to the realm of cancer biology. The authors reveal that the UPR^mt pathway similarly drives epithelial-to-mesenchymal transition (EMT) in cancer cells, a process antithetical to MET that facilitates cell migration, invasion, and metastatic dissemination. By enhancing EMT, UPR^mt activation emerges as a potential accelerator of tumour progression, identifying it as a promising therapeutic target to counteract metastasis. Intriguingly, such dual roles of UPR^mt—suppressing pluripotency via MET blockade and promoting cancer aggressiveness via EMT enhancement—highlight its versatile and context-dependent functions.
At its core, this study redefines the mitochondrial unfolded protein response from a reactive, damage-control pathway into a finely tuned modulator of cellular identity. The crosstalk between mitochondrial proteostasis, metabolic flux, and chromatin state orchestrated through UPR^mt challenges us to rethink how intracellular organellar stress responses are integrated into developmental and pathological programs. The transient nature of UPR^mt activation during reprogramming suggests a window of plasticity where mitochondrial signals can decisively tip the balance toward or away from pluripotency, shaping cell fate outcomes with exquisite precision.
Historically, the mesenchymal-to-epithelial transition has been recognized as indispensable for the generation of induced pluripotent stem cells (iPSCs), serving as a hallmark of early reprogramming. The discovery that mitochondrial proteostasis, via UPR^mt, impinges directly on MET offers a new layer of regulation that can explain some of the inefficiencies and heterogeneity observed in reprogramming protocols. Targeting components of the UPR^mt pathway or its downstream effectors like c-Jun could therefore enhance the efficiency and fidelity of induced pluripotency, opening new avenues for regenerative medicine and therapeutic cell engineering.
From a molecular perspective, the interplay between mitochondrial stress signaling and nuclear chromatin remodeling extends our understanding of metabolic-epigenetic coupling. Acetyl-CoA has emerged as a pivotal metabolite bridging cellular metabolism and the epigenetic landscape. By revealing that UPR^mt modulates acetyl-CoA metabolism to exert epigenetic control, this study positions mitochondria as key arbiters of gene expression beyond energy metabolism, directly influencing histone modification and transcriptional programs.
Moreover, the newfound role of c-Jun as a metabolic-epigenetic regulator downstream of UPR^mt adds complexity to its well-documented functions in stress responses and oncogenesis. This crosstalk elucidates how stress-activated transcription factors may coordinate metabolic rewiring with chromatin state changes, serving as integrators of intracellular signaling and gene regulatory networks critical for both normal development and disease progression.
Given the centrality of EMT in tumour metastasis, the link between UPR^mt and enhanced EMT underscores potential clinical significance. Therapies directed at modulating mitochondrial proteostasis or selectively inhibiting UPR^mt activation could thwart cancer invasiveness and improve patient outcomes. This insight encourages a paradigm shift, where mitochondrial signaling pathways become focal points in the design of anticancer strategies targeting metastatic dissemination rather than proliferative control alone.
The study also prompts intriguing questions about the possible roles of UPR^mt in other developmental and pathological contexts. For instance, does transient UPR^mt activation similarly regulate stem cell transitions in adult tissues? Could aberrations in mitochondrial proteostasis underlie differentiation defects or contribute to degenerative diseases through epigenetic dysregulation? These provocative considerations set the stage for future research to disentangle the versatile functions of mitochondrial-nuclear communication in health and disease.
In summary, Ying et al. provide compelling evidence that the mitochondrial unfolded protein response is a hitherto unappreciated gatekeeper of pluripotency acquisition and cellular plasticity through its modulation of mesenchymal-to-epithelial transition. By bridging mitochondrial stress signals with metabolic and epigenetic remodeling via c-Jun and acetyl-CoA metabolism, this work charts a transformative path in our understanding of cell fate regulation. Furthermore, the UPR^mt’s involvement in promoting epithelial-to-mesenchymal transition in cancer cells reveals its dualistic nature in tissue homeostasis and disease, offering novel targets for therapeutic intervention.
This landmark study not only expands the functional repertoire of the UPR^mt pathway beyond mitochondrial maintenance but also highlights its integration into fundamental biological processes central to organismal development and oncogenesis. As researchers delve deeper into mitochondrial signaling networks, the insights gleaned here will undoubtedly fuel innovative approaches harnessing mitochondrial dynamics to modulate stem cell states and combat metastatic cancer.
Subject of Research: Mitochondrial unfolded protein response regulation of pluripotency acquisition and cell state transitions in somatic cell reprogramming; role in cancer metastasis.
Article Title: The mitochondrial unfolded protein response inhibits pluripotency acquisition and mesenchymal-to-epithelial transition in somatic cell reprogramming.
Article References:
Ying, Z., Xin, Y., Liu, Z. et al. The mitochondrial unfolded protein response inhibits pluripotency acquisition and mesenchymal-to-epithelial transition in somatic cell reprogramming. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01261-6
Image Credits: AI Generated
Tags: adaptive responses in cellular biologyc-Myc in reprogrammingcellular reprogramming mechanismsimplications for cancer metastasismitochondrial integrity and longevitymitochondrial stress and cell fatemitochondrial unfolded protein responsemouse embryonic fibroblasts studypluripotent stem cell inductionproteostasis during cell transitionstem cell biology advancementsUPR^mt role in mammalian development
