Mitochondrial miRNA Determines Chemoresistance by Reprogramming Metabolism and Regulating Mitochondrial Transcription

Fan, ST; Tian, Tian; Chen, Weixiong; Lv, Xiaobin; Lei, Xinyuan; Zhang, Hanqing; Sun, Sheng; Cai, Lei; Pan, Guokai; He, Lizhi; Ou, Zhanpeng; Lin, Xinyu; Wang, Xinhui; Perez, Monika W.; Tu, Zhiming; Ferrone, Soldano; Tannous, Bakhos A.; Li, Jinsong

doi:10.1158/0008-5472.can-18-2505

Cited by 101 publications

(79 citation statements)

References 48 publications

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“…For instance, it was demonstrated that mito-miR-2392 regulates the cisplatin resistance by reprogramming the balance between OXPHOS and glycolysis in tongue squamous cell carcinoma (TSCC) cells. Furthermore, in a retrospective analysis of TSCC patient tumor revealed a significant association of miR2392 and the expression of mitochondrial gene with chemosensitivity and overall survival (91).…”

Section: Mtorc1 and Mitochondrial Regulation By Mirnas In Cancermentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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Continuous proliferation of tumor cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. This energetic adaptation often comprises deregulated glucose uptake and lactate production in the presence of oxygen, a process known as the "Warburg effect." For many years it was thought that the Warburg effect was a result of mitochondrial damage, however, unlike this proposal tumor cell mitochondria maintain their functionality, and is essential for integrating a variety of signals and adapting the metabolic activity of the tumor cell. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of numerous cellular processes implicated in proliferation, metabolism, and cell growth. mTORC1 controls cellular metabolism mainly by regulating the translation and transcription of metabolic genes, such as peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1 α (HIF-1α). Interestingly it has been shown that mTORC1 regulates mitochondrial metabolism, thus representing an important regulator in mitochondrial function. Here we present an overview on the role of mTORC1 in the regulation of mitochondrial functions in cancer, considering new evidences showing that mTORC1 regulates the translation of nucleus-encoded mitochondrial mRNAs that result in an increased ATP mitochondrial production. Moreover, we discuss the relationship between mTORC1 and glutaminolysis, as well as mitochondrial metabolites. In addition, mitochondrial fission processes regulated by mTORC1 and its impact on cancer are discussed. Finally, we also review the therapeutic efficacy of mTORC1 inhibitors in cancer treatments, considering its use in combination with other drugs, with particular focus on cellular metabolism inhibitors, that could help improve their anti neoplastic effect and eliminate cancer cells in patients. de la Cruz López et al. mTORC1 and Mitochondrial Functions Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a shared affiliation, though no other collaboration, with with several of the authors AG and KC.

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Section: Mtorc1 and Mitochondrial Regulation By Mirnas In Cancermentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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“…The miRNAs identified in the mitochondria are collectively termed mitochondrial microRNAs (mitomiRs; Bandiera et al, 2011). This metabolic reprogramming is believed to trigger chemo-resistance during cisplatin chemotherapy in tongue squamous cell carcinoma (Fan et al, 2019). The exact mechanism of nuclear encoded mitomiRs transport is largely unknown, and some studies suggest that Environmental and Molecular Mutagenesis.…”

Section: Small Noncoding Rnasmentioning

confidence: 99%

“…For instance, specific base pairing between miR-2392 and mtDNA in an AGO2-dependent manner inhibits mtDNA transcription partially, resulting in the downregulation of OXPHOS and the concomitant upregulation of glycolysis. This metabolic reprogramming is believed to trigger chemo-resistance during cisplatin chemotherapy in tongue squamous cell carcinoma (Fan et al, 2019). At the translational level, mitomiRs downregulate most mtDNA encoded proteins.…”

Section: Small Noncoding Rnasmentioning

confidence: 99%

Mitochondrial DNA: Epigenetics and environment

Sharma

Pasala

Prakash

2019

Environ and Mol Mutagen

106

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Maintenance of the mitochondrial genome is essential for proper cellular function. For this purpose, mitochondrial DNA (mtDNA) needs to be faithfully replicated, transcribed, translated, and repaired in the face of constant onslaught from endogenous and environmental agents. Although only 13 polypeptides are encoded within mtDNA, the mitochondrial proteome comprises over 1500 proteins that are encoded by nuclear genes and translocated to the mitochondria for the purpose of maintaining mitochondrial function. Regulation of mtDNA and mitochondrial proteins by epigenetic changes and post‐translational modifications facilitate crosstalk between the nucleus and the mitochondria and ultimately lead to the maintenance of cellular health and homeostasis. DNA methyl transferases have been identified in the mitochondria implicating that methylation occurs within this organelle; however, the extent to which mtDNA is methylated has been debated for many years. Mechanisms of demethylation within this organelle have also been postulated, but the exact mechanisms and their outcomes is still an active area of research. Mitochondrial dysfunction in the form of altered gene expression and ATP production, resulting from epigenetic changes, can lead to various conditions including aging‐related neurodegenerative disorders, altered metabolism, changes in circadian rhythm, and cancer. Here, we provide an overview of the epigenetic regulation of mtDNA via methylation, long and short noncoding RNAs, and post‐translational modifications of nucleoid proteins (as mitochondria lack histones). We also highlight the influence of xenobiotics such as airborne environmental pollutants, contamination from heavy metals, and therapeutic drugs on mtDNA methylation. Environ. Mol. Mutagen., 60:668–682, 2019. © 2019 Wiley Periodicals, Inc.

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“…Several mitomiRs may be originated from mitochondrial genome-derived mRNA molecules. MitomiRs have been mostly found to post-translationally regulate gene expression inside the mitochondrion [31,32]. In addition, some of them may target nuclear-encoded mRNAs localized on the mitochondrial surface ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial MiRNA in Cardiovascular Function and Disease

Song

Zhang

2019

Cells

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MicroRNAs (miRNAs) are small noncoding RNAs functioning as crucial post-transcriptional regulators of gene expression involved in cardiovascular development and health. Recently, mitochondrial miRNAs (mitomiRs) have been shown to modulate the translational activity of the mitochondrial genome and regulating mitochondrial protein expression and function. Although mitochondria have been verified to be essential for the development and as a therapeutic target for cardiovascular diseases, we are just beginning to understand the roles of mitomiRs in the regulation of crucial biological processes, including energy metabolism, oxidative stress, inflammation, and apoptosis. In this review, we summarize recent findings regarding how mitomiRs impact on mitochondrial gene expression and mitochondrial function, which may help us better understand the contribution of mitomiRs to both the regulation of cardiovascular function under physiological conditions and the pathogenesis of cardiovascular diseases.

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Mitochondrial miRNA Determines Chemoresistance by Reprogramming Metabolism and Regulating Mitochondrial Transcription

Cited by 101 publications

References 48 publications

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

Mitochondrial DNA: Epigenetics and environment

Mitochondrial MiRNA in Cardiovascular Function and Disease

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