Mitochondrial Stress Response and Cancer

O’Malley, Jordan; Kumar, Rahul; Inigo, Joseph R.; Yadava, Nagendra; Chandra, Dhyan

doi:10.1016/j.trecan.2020.04.009

Cited by 101 publications

(69 citation statements)

References 156 publications

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“…Mitochondria have developed several stress response mechanisms to maintain their homeostasis 31 – 33 , 12 . In addition to selective removal of damaged mitochondria through mitophagy, first-line defense mechanisms against mitochondrial damage occur on a molecular level via proteolytic machineries consisting of chaperones and proteases.…”

Section: Discussionmentioning

confidence: 99%

“…As cancer cells are continuously exposed to various cytotoxic stressors in harsh tumor microenvironments, including hypoxia, nutrient deprivation, and oxidative stress, mitochondria must adapt to changes and buffer stress conditions to promote cancer cell proliferation and survival 11 , 12 . Indeed, mitochondrial stress responses are linked to alterations in mitochondrial functions required for tumor progression via adaptations to changing metabolic demands, regulation of cell death pathways, and contributions to chemoresistance 4 .…”

Section: Introductionmentioning

confidence: 99%

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LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

et al. 2021

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Mitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

et al. 2021

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“…mtROS accumulation may damage the organelle, exacerbating the mitochondrial oncogenic stress. Under these conditions, the cancer cells active the mitochondrial stress responses, such as mitophagy and UPR mt , to restore the mitochondrial integrity potentiating the cellular survivor and resistance to stress [ 133 ]. mtROS produced by cancer cells are signaling molecules released in tumor microenvironment to condition cancer-associated cells and tumor-infiltrating leukocytes [ 117 ].…”

Section: Mitochondrial Oxidative Stress and Mito-inflammation In Imentioning

confidence: 99%

Mitochondrial Oxidative Stress and “Mito-Inflammation”: Actors in the Diseases

et al. 2021

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A decline in mitochondrial redox homeostasis has been associated with the development of a wide range of inflammatory-related diseases. Continue discoveries demonstrate that mitochondria are pivotal elements to trigger inflammation and stimulate innate immune signaling cascades to intensify the inflammatory response at front of different stimuli. Here, we review the evidence that an exacerbation in the levels of mitochondrial-derived reactive oxygen species (ROS) contribute to mito-inflammation, a new concept that identifies the compartmentalization of the inflammatory process, in which the mitochondrion acts as central regulator, checkpoint, and arbitrator. In particular, we discuss how ROS contribute to specific aspects of mito-inflammation in different inflammatory-related diseases, such as neurodegenerative disorders, cancer, pulmonary diseases, diabetes, and cardiovascular diseases. Taken together, these observations indicate that mitochondrial ROS influence and regulate a number of key aspects of mito-inflammation and that strategies directed to reduce or neutralize mitochondrial ROS levels might have broad beneficial effects on inflammatory-related diseases.

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“…Furthermore, malignant cells raise the mitochondrial apoptotic threshold by activating mitochondrial maintenance programs, which is important for enhancing cancer cell survival, proliferation, and metastasis. Other organelles such as the nucleus and endoplasmic reticulum and their crosstalk with mitochondria are essential components of cancer cell physiology such as survival, proliferation, metastasis, and stemness ( 51 ). In extreme environmental conditions such as hypoxia and acidic shift of the environment, nutritional deficiency and radiation, GSCs use specific protective mechanisms such as activation of stress response pathways to counteract the anti-cancer effects of endogenous stressors such as increased ROS production and exogenous stressors such as chemotherapy agents.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria’s Role in the Maintenance of Cancer Stem Cells in Glioblastoma

et al. 2021

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Glioblastoma (GBM), one of the deadliest primary brain malignancies, is characterized by a high recurrence rate due to its limited response to existing therapeutic strategies such as chemotherapy, radiation therapy, and surgery. Several mechanisms and pathways have been identified to be responsible for GBM therapeutic resistance. Glioblastoma stem cells (GSCs) are known culprits of GBM resistance to therapy. GSCs are characterized by their unique self-renewal, differentiating capacity, and proliferative potential. They form a heterogeneous population of cancer stem cells within the tumor and are further divided into different subpopulations. Their distinct molecular, genetic, dynamic, and metabolic features distinguish them from neural stem cells (NSCs) and differentiated GBM cells. Novel therapeutic strategies targeting GSCs could effectively reduce the tumor-initiating potential, hence, a thorough understanding of mechanisms involved in maintaining GSCs’ stemness cannot be overemphasized. The mitochondrion, a regulator of cellular physiological processes such as autophagy, cellular respiration, reactive oxygen species (ROS) generation, apoptosis, DNA repair, and cell cycle control, has been implicated in various malignancies (for instance, breast, lung, and prostate cancer). Besides, the role of mitochondria in GBM has been extensively studied. For example, when stressors, such as irradiation and hypoxia are present, GSCs utilize specific cytoprotective mechanisms like the activation of mitochondrial stress pathways to survive the harsh environment. Proliferating GBM cells exhibit increased cytoplasmic glycolysis in comparison to terminally differentiated GBM cells and quiescent GSCs that rely more on oxidative phosphorylation (OXPHOS). Furthermore, the Warburg effect, which is characterized by increased tumor cell glycolysis and decreased mitochondrial metabolism in the presence of oxygen, has been observed in GBM. Herein, we highlight the importance of mitochondria in the maintenance of GSCs.

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Mitochondrial Stress Response and Cancer

Cited by 101 publications

References 156 publications

LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

Mitochondrial Oxidative Stress and “Mito-Inflammation”: Actors in the Diseases

Mitochondria’s Role in the Maintenance of Cancer Stem Cells in Glioblastoma

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