Mitochondrial unfolded protein response gene CLPP changes mitochondrial dynamics and affects mitochondrial function

Wu, Guijun; Xiong, Qing; Xiao-jun, Wei; Wang, Ye; Hu, Xuemei; He, Guangzhen; Liu, LinJie; Lai, QianHui; Dai, Zhijiang; Anushesh, Dhakal; Xu, Yancheng

doi:10.7717/peerj.7209

Cited by 16 publications

(10 citation statements)

References 48 publications

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“…Thus, the results suggest that mtROS is critical for maintaining mitochondrial membrane potential but how mtROS plays a role in maintaining mitochondrial quality is unclear. UPRmt, as an essential quality control mechanism for maintaining mitochondrial protein homeostasis, is closely related to mitochondrial membrane potential [50][51][52]. However, whether mtROS generated during Table 3: HTRA2 in the intermembrane space of mitochondria protein and control group normalization (X À ± SD).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial ROS Produced by Skeletal Muscle Mitochondria Promote the Decisive Signal for UPRmt Activation

Wang

Bai

Song

et al. 2022

BioMed Research International

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The mitochondrial unfolded protein response (UPRmt) can repair and remove misfolded or unfolded proteins in mitochondria and enhance mitochondrial protein homeostasis. Reactive oxygen species (ROS) produced by regular exercise is a crucial signal for promoting health, and skeletal muscle mitochondria are the primary source of ROS during exercise. To verify whether UPRmt is related to ROS produced by mitochondria in skeletal muscle during regular exercise, we adapted MitoTEMPO, mitochondrially targeted antioxidants, and ROS production by mitochondria. Our results showed that mitochondrial ROS is the key factor for activating UPRmt in different pathways.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial ROS Produced by Skeletal Muscle Mitochondria Promote the Decisive Signal for UPRmt Activation

Wang

Bai

Song

et al. 2022

BioMed Research International

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“…Recent preclinical and clinical data have hinted at an efficacy of ONC201 in several solid cancers including GBM [21][22][23]25,27 . Originally identified as an inducer of TRAIL, ONC201 inhibits D2-like dopamine receptors DRD2 and DRD3 and activates the mitochondrial protease ClpP, a key player in the mitochondrial unfolded protein response 52,53 . So far, clinical trials using ONC201 against GBM have shown pharmacodynamic activity in biomarker-defined recurrent GBM patients, as well as in pediatric and adult H3 K27M-mutant glioma 22,26,27 .…”

Section: Discussionmentioning

confidence: 99%

Synergistic Effects of the DRD2/3 Antagonist ONC201 and Radiation in Glioblastoma

Bhat

Ioannidis

et al. 2020

Preprint

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BackgroundGlioblastoma (GBM) is the deadliest of all brain cancers in adults. The current standard-of-care is surgery followed by radiotherapy and temozolomide, leading to a median survival time of only 15 months. GBM are organized hierarchically with a small number of glioma-initiating cells, responsible for therapy resistance and tumor recurrence, suggesting that targeting glioma-initiating cells could improve treatment response. ONC201 is a first-in-class anti-tumor agent with clinical efficacy in some forms of high-grade gliomas. Here we test its efficacy against GBM in combination with radiation.MethodsUsing patient-derived GBM lines and mouse models of GBM we test the effects of radiation and ONC201 on GBM self - renewal in vitro and survival in vivo. A possible resistance mechanism is investigated using RNA-Sequencing.ResultsTreatment of GBM cells with ONC201 reduced self-renewal, clonogenicity and cell viability in vitro. ONC201 exhibited anti-tumor effects on radioresistant GBM cells indicated by reduced self-renewal in secondary and tertiary glioma spheres. Combined treatment with ONC201 and radiation prolonged survival in syngeneic and patient-derived orthotopic xenograft mouse models of GBM. Subsequent transcriptome analyses after combined treatment revealed shifts in gene expression signatures related to quiescent GBM populations, GBM plasticity, and GBM stem cells.ConclusionsOur findings suggest that combined treatment with the DRD2/3 antagonist ONC201 and radiation improves the efficacy of radiation against GBM in vitro and in vivo through suppression of GICs without increasing toxicity in mouse models of GBM. A clinical assessment of this novel combination therapy against GBM is further warranted.Key points- Combined treatment of ONC201 and radiation exhibit anti-tumor effects on cells from primary and recurrent GBM- Combined treatment significantly prolongs survival in vivo- Combined treatment potentially targets the quiescent GBM cell populationImportance of the StudyThe survival rates for patients with GBM are unacceptably low and novel treatment approaches are needed. This study provides evidence that a combination of radiation and the dopamine receptor antagonist ONC201 significantly prolongs survival in mouse models of glioma.

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“…HSP60, HSP72, and HSP70, which are mitochondrial chaperone proteins, substantially impact T2D (Lee et al, 2011;Kim et al, 2013;Kleinridders et al, 2013;Henstridge et al, 2014;Mottis et al, 2014;Lee et al, 2015;Aluksanasuwan et al, 2017). Moreover, high levels of mitochondrial proteases, including LONP1, CLPP, and OMA1, are also involved in protective action in T2D (Lee et al, 2011;Lee et al, 2015;Wu et al, 2019;Kalvala et al, 2020). (Figure 2).…”

Section: Cross Talk Of Upr Mt and Upr Ermentioning

confidence: 99%

UPRmt and coordinated UPRER in type 2 diabetes

Kang

Chen

et al. 2022

Front. Cell Dev. Biol.

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The mitochondrial unfolded protein response (UPRmt) is a molecular mechanism that maintains mitochondrial proteostasis under stress and is closely related to various metabolic diseases, such as type 2 diabetes (T2D). Similarly, the unfolded protein response of the endoplasmic reticulum (UPRER) is responsible for maintaining proteomic stability in the endoplasmic reticulum (ER). Since the mitochondria and endoplasmic reticulum are the primary centers of energy metabolism and protein synthesis in cells, respectively, a synergistic mechanism must exist between UPRmt and UPRER to cooperatively resist stresses such as hyperglycemia in T2D. Increasing evidence suggests that the protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) signaling pathway is likely an important node for coordinating UPRmt and UPRER. The PERK pathway is activated in both UPRmt and UPRER, and its downstream molecules perform important functions. In this review, we discuss the mechanisms of UPRmt, UPRER and their crosstalk in T2D.

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Mitochondrial unfolded protein response gene CLPP changes mitochondrial dynamics and affects mitochondrial function

Cited by 16 publications

References 48 publications

Mitochondrial ROS Produced by Skeletal Muscle Mitochondria Promote the Decisive Signal for UPRmt Activation

Mitochondrial ROS Produced by Skeletal Muscle Mitochondria Promote the Decisive Signal for UPRmt Activation

Synergistic Effects of the DRD2/3 Antagonist ONC201 and Radiation in Glioblastoma

UPRmt and coordinated UPRER in type 2 diabetes

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