Mitochondrial quality control proteases and their modulation for cancer therapy

Zhang, Jiangnan; Qiao, Wenliang; Luo, Youfu

doi:10.1002/med.21929

Cited by 25 publications

(17 citation statements)

References 202 publications

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“…While the exact roles of ClpP in tumorigenesis are not clearly established, emerging evidence demonstrate that ClpP is overexpressed in multiple malignancies including breast cancers [ 261 , 262 , 263 ]. Recent analysis of TCGA database also confirmed that ClpP is overexpressed in breast and other cancers [ 264 ]. In addition, a high level of ClpP expression is associated with the disease stage, metastasis, poor prognosis and is proposed as a prognostic marker in breast cancers [ 261 , 265 , 266 ].…”

Section: Clppmentioning

confidence: 89%

“…Since ClpP activators, but not ClpP inhibitors, show cytotoxicity in breast cancers, we will focus on ClpP activators in this review (for ClpP inhibitors, we refer readers to other excellent reviews [ 233 , 264 , 266 ]. There are three classes of ClpP agonists: acyldepsipeptide antibiotics (ADEPs), ONC201 and its analogs (imipridones), and TR compounds.…”

Section: Clppmentioning

confidence: 99%

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Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer

Wedam

Greer

Wisniewski

et al. 2023

Cancers

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Breast cancer is the most frequently diagnosed malignancy worldwide and the leading cause of cancer mortality in women. Despite the recent development of new therapeutics including targeted therapies and immunotherapy, triple-negative breast cancer remains an aggressive form of breast cancer, and thus improved treatments are needed. In recent decades, it has become increasingly clear that breast cancers harbor metabolic plasticity that is controlled by mitochondria. A myriad of studies provide evidence that mitochondria are essential to breast cancer progression. Mitochondria in breast cancers are widely reprogrammed to enhance energy production and biosynthesis of macromolecules required for tumor growth. In this review, we will discuss the current understanding of mitochondrial roles in breast cancers and elucidate why mitochondria are a rational therapeutic target. We will then outline the status of the use of mitochondria-targeting drugs in breast cancers, and highlight ClpP agonists as emerging mitochondria-targeting drugs with a unique mechanism of action. We also illustrate possible drug combination strategies and challenges in the future breast cancer clinic.

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Section: Clppmentioning

confidence: 89%

Section: Clppmentioning

confidence: 99%

Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer

Wedam

Greer

Wisniewski

et al. 2023

Cancers

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“…Severe asthma is associated with energy metabolism dysfunction (Xu et al, 2022), and mitochondria play an important role in energy metabolism (Zhang et al, 2022). Bronchial epithelial cells play an essential role in asthma and mitochondrial dysfunction is implicated in asthmatic bronchial epithelial cells (AghapourRAPS et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondria, as fundamental organelles for cellular and systemic metabolism, are critical in the fundamental biological processes including cellular differentiation, apoptosis, autophagy and hypoxic stress responses (AghapourRAPS et al, 2020;Larson-Casey et al, 2020;Zhang et al, 2022). Mitochondria dysfunction has been linked to a variety of disorders including cardiovascular disease, and cancer (Zhang et al, 2021;Vikramdeo et al, 2022;Liu et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Mitochondria dysfunction in airway epithelial cells is associated with type 2-low asthma

Gao

Chen

et al. 2023

Front. Genet.

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Background: Type 2 (T2)-low asthma can be severe and corticosteroid-resistant. Airway epithelial cells play a pivotal role in the development of asthma, and mitochondria dysfunction is involved in the pathogenesis of asthma. However, the role of epithelial mitochondria dysfunction in T2-low asthma remains unknown.Methods: Differentially expressed genes (DEGs) were identified using gene expression omnibus (GEO) dataset GSE4302, which is originated from airway epithelial brushings from T2-high (n = 22) and T2-low asthma patients (n = 20). Gene set enrichment analysis (GSEA) was implemented to analyze the potential biological pathway involved between T2-low and T2-high asthma. T2-low asthma related genes were identified using weighted gene co-expression network analysis (WGCNA). The mitochondria-related genes (Mito-RGs) were referred to the Molecular Signatures Database (MSigDB). T2-low asthma related mitochondria (T2-low-Mito) DEGs were obtained by intersecting the DEGs, T2-low asthma related genes, and Mito-RGs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed to further explore the potential function of the T2-low-Mito DEGs. In addition, the hub genes were further identified by protein-protein interaction (PPI), and the expressions of hub genes were verified in another GEO dataset GSE67472 and bronchial brushings from patients recruited at Tongji Hospital.Results: Six hundred and ninety-two DEGs, including 107 downregulated genes and 585 upregulated genes were identified in airway epithelial brushings from T2-high and T2-low asthma patients included in GSE4302 dataset. GSEA showed that mitochondrial ATP synthesis coupled electron transport is involved in T2-low asthma. Nine hundred and four T2-low asthma related genes were identified using WGCNA. Twenty-two T2-low-Mito DEGs were obtained by intersecting the DEGs, T2-low asthma and Mito-RGs. The GO enrichment analysis of the T2-low-Mito DEGs showed significant enrichment of mitochondrial respiratory chain complex assembly, and respiratory electron transport chain. PPI network was constructed using 22 T2-low-Mito DEGs, and five hub genes, ATP5G1, UQCR10, NDUFA3, TIMM10, and NDUFAB1, were identified. Moreover, the expression of these hub genes was validated in another GEO dataset, and our cohort of asthma patients.Conclusion: This study suggests that mitochondria dysfunction contributes to T2-low asthma.

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“…Precise delivery of anti-cancer drugs based on nano-drug delivery systems to subcellular targets, such as mitochondria, lysosomes, and nuclei, has already been considered as an excellent cancer treatment strategy ( Yang L. et al, 2022 ; Zhang J. et al, 2022 ; Wang et al, 2022 ). Mitochondria, the powerhouse of aerobic metabolism, exert an essential role in cellular physiological and pathological processes ( Song et al, 2019 ; Zhang S. et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress induced by berberine-based mitochondria-targeted low temperature photothermal therapy

Song

Yang

et al. 2023

Front. Chem.

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Introduction: Mitochondria-targeted low-temperature photothermal therapy (LPTT) is a promising strategy that could maximize anticancer effects and overcome tumor thermal resistance. However, the successful synthesis of mitochondria-targeted nanodrug delivery system for LPTT still faces diverse challenges, such as laborious preparations processes, low drug-loading, and significant systemic toxicity from the carriers.Methods: In this study, we used the tumor-targeting folic acid (FA) and mitochondria-targeting berberine (BBR) derivatives (BD) co-modified polyethylene glycol (PEG)-decorated graphene oxide (GO) to synthesize a novel mitochondria-targeting nanocomposite (GO-PEG-FA/BD), which can effectively accumulate in mitochondria of the osteosarcoma (OS) cells and achieve enhanced mitochondria-targeted LPTT effects with minimal cell toxicity. The mitochondria-targeted LPTT effects were validated both in vitro and vivo.Results:In vitro experiments, the nanocomposites (GO-PEG-FA/BD) could eliminate membrane potential (ΔΨm), deprive the ATP of cancer cells, and increase the levels of reactive oxygen species (ROS), which ultimately induce oxidative stress damage. Furthermore, in vivo results showed that the enhanced mitochondria-targeted LPTT could exert an excellent anti-cancer effect with minimal toxicity.Discussion: Taken together, this study provides a practicable strategy to develop an ingenious nanoplatform for cancer synergetic therapy via mitochondria-targeted LPTT, which hold enormous potential for future clinical translation.

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Mitochondrial quality control proteases and their modulation for cancer therapy

Cited by 25 publications

References 202 publications

Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer

Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer

Mitochondria dysfunction in airway epithelial cells is associated with type 2-low asthma

Oxidative stress induced by berberine-based mitochondria-targeted low temperature photothermal therapy

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