Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors

Anderson, Grace R.; Wardell, Suzanne E.; Çakır, Merve; Yip, Catherine; Ahn, Yeong-ran; Ali, Moiez; Yllanes, Alexander P.; Chao, Christina A.; McDonnell, Donald P.; Wood, Kris C.

doi:10.1038/s41467-018-04033-x

Cited by 112 publications

(79 citation statements)

References 49 publications

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“…It has been established that the alteration of mitochondrial dynamics impact tumor development broadly. Alterations to the mitochondrial dynamic network also result in specific therapeutic susceptibilities, in particular, tumors with increased mitochondrial fragmentation or connectivity are hypersensitive to SMAC mimetics and induce apoptosis by blocking the action of inhibitor of apoptosis proteins (IAPs) (124). On the other hand, it was demonstrated that Drp1 expression was strongly increased in distant metastasis of hepatocellular carcinoma (HCC) compared to primary tumors.…”

Section: Mtorc1 and Mitochondrial Dynamic 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 Dynamic In Cancermentioning

confidence: 99%

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

et al. 2019

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“…Moreover, Ang II is a potent mediator of oxidative stress and oxidant signaling leading to vascular premature senescence (Andrés, 2014). In this study, we showed that short-term exposure (1 day Mitochondria exist in a dynamic equilibrium between fragmented and fused states, and mitochondrial dynamics is controlled by fission and fusion (Anderson et al, 2018;Shi et al, 2018). Increased mitochondrial fission and/or attenuated fusion lead to mitochondrial fragmentation and disrupt cellular physiological function (Caja et al, 2017).…”

Section: Discussionmentioning

confidence: 79%

“…Mitochondria play important roles in regulating critical cellular, physiological, and pathophysiological processes (Tezze et al, 2017;Anderson et al, 2018). Alterations in mitochondrial dynamics, which is regulated mainly by the processes of fission and fusion, are implicated in various human diseases including cancer and neurologic and cardiovascular diseases (Anderson et al, 2018;Abuarab et al, 2017;Vásquez-Trincado et al, 2016). Previous studies have demonstrated that dysregulation of mitochondrial dynamics is a key feature of aging (Anderson et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Alterations in mitochondrial dynamics, which is regulated mainly by the processes of fission and fusion, are implicated in various human diseases including cancer and neurologic and cardiovascular diseases (Anderson et al, 2018;Abuarab et al, 2017;Vásquez-Trincado et al, 2016). Previous studies have demonstrated that dysregulation of mitochondrial dynamics is a key feature of aging (Anderson et al, 2018). Moreover, mitochondria are a major source of ROS, and mitochondrial dysfunction may leads to aberrant ROS production (Murphy 2009).…”

Section: Introductionmentioning

confidence: 99%

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eIF5a reduction via decreased Klf5 leads to cell senescence by mitochondrial fission in VSMCs

Zheng

et al. 2019

Preprint

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Though dysregulation of mitochondrial dynamics has been linked to cellular senescence, which contributes to advanced age-related disorders, it is unclear how Klf5, an essential transcriptional factor of cardiovascular remodeling, mediates the link between mitochondrial dynamics and vascular smooth muscle cell (VSMC) senescence. Here we show that Klf5 downregulation in VSMCs is correlated with rupture of abdominal aortic aneurysm (AAA), an age-related vascular disease. Mice lacking Klf5 in VSMCs exacerbate vascular senescence and progression of Ang II-induced AAA by facilitating ROS formation. Klf5 knockdown enhances, while Klf5 overexpression suppresses mitochondrial fission. Mechanistically, Klf5 activates eIF5a transcription through binding to the promoter of eIF5a, which in turn preserves mitochondrial integrity by interacting with Mfn1. Accordingly, decreased expression of eIF5a elicited by Klf5 downregulation leads to mitochondrial fission and excessive ROS production. Inhibition of mitochondrial fission decreases ROS production and VSMC senescence. Our studies provide a potential therapeutic target for age-related vascular disorders.

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“…Regulation of mitochondrial dynamics is essential for development (Chen et al, 2003; Ishihara et al, 2009; Waterham et al, 2007) and dysregulation of its machinery is implicated in a wide range of human diseases, including neuropathies, type II diabetes, and cancer (Anderson et al, 2018; Ranieri et al, 2013; Rovira-Llopis et al, 2017). However, the role of mitochondrial dynamics in other contexts, such as epithelial repair is still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Drp1-mediated mitochondrial fission regulates calcium and F-actin dynamics during wound healing

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Carvalho

Gagliardi

et al. 2019

Preprint

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Mitochondria adapt to cellular needs by changes in morphology through fusion and fission events, referred to as mitochondrial dynamics. Mitochondrial function and morphology are intimately connected and the dysregulation of mitochondrial dynamics is linked to several human diseases. In this work, we investigated the role of mitochondrial dynamics in wound healing in the Drosophila embryonic epidermis. Mutants for mitochondrial fusion and fission proteins fail to close their wounds, indicating that the regulation of mitochondrial dynamics is required for wound healing. By live-imaging, we found that loss of function of the mitochondrial fission protein Dynamin-related protein 1 (Drp1) compromises the increase of cytosolic and mitochondrial calcium upon wounding and leads to F-actin defects at the wound edge, culminating in wound healing impairment. Our results highlight a new role for mitochondrial dynamics in the regulation of calcium and F-actin during epithelial repair.SummaryWe show that mitochondrial dynamics proteins are required for epithelial repair. In particular, Drp1 loss-of-function leads to defects in the dynamics of cytosolic and mitochondrial calcium and F-actin upon wounding.

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Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors

Cited by 112 publications

References 49 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

eIF5a reduction via decreased Klf5 leads to cell senescence by mitochondrial fission in VSMCs

Drp1-mediated mitochondrial fission regulates calcium and F-actin dynamics during wound healing

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