The Role of Mitochondrial Dynamics and Mitophagy in Carcinogenesis, Metastasis and Therapy

Wang, Yigang; Liu, Huihui; Cao, Yuting; Zhang, Leilei; Huang, Fang; Yi, Cong

doi:10.3389/fcell.2020.00413

Cited by 97 publications

(85 citation statements)

References 136 publications

(148 reference statements)

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“…Mitophagy, the specialized autophagy that targets defective mitochondria, is a cardinal feature of mitochondrial quality control since it is responsible for the clearance of damaged mitochondria. Defective mitophagy is usually linked to the impairment of mitochondrial functions [ 85 , 86 ].…”

Section: Discussionmentioning

confidence: 99%

Tafazzin Mutation Affecting Cardiolipin Leads to Increased Mitochondrial Superoxide Anions and Mitophagy Inhibition in Barth Syndrome

Petit

Ardilla-Osorio

Penalvia

et al. 2020

Cells

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Tafazzin is a phospholipid transacylase that catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mutations of the tafazzin gene cause Barth syndrome, which is characterized by mitochondrial dysfunction and dilated cardiomyopathy, leading to premature death. However, the molecular mechanisms underlying the cause of mitochondrial dysfunction in Barth syndrome remain poorly understood. We again highlight the fact that the tafazzin deficiency is also linked to defective oxidative phosphorylation associated with oxidative stress. All the mitochondrial events are positioned in a context where mitophagy is a key element in mitochondrial quality control. Here, we investigated the role of tafazzin in mitochondrial homeostasis dysregulation and mitophagy alteration. Using a HeLa cell model of tafazzin deficiency, we show that dysregulation of tafazzin in HeLa cells induces alteration of mitophagy. Our findings provide some additional insights into mitochondrial dysfunction associated with Barth syndrome, but also show that mitophagy inhibition is concomitant with apoptosis dysfunction through the inability of abnormal mitochondrial cardiolipin to assume its role in cytoplasmic signal transduction. Our work raises hope that pharmacological manipulation of the mitophagic pathway together with mitochondrially targeted antioxidants may provide new insights leading to promising treatment for these highly lethal conditions.

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Section: Discussionmentioning

confidence: 99%

Tafazzin Mutation Affecting Cardiolipin Leads to Increased Mitochondrial Superoxide Anions and Mitophagy Inhibition in Barth Syndrome

Petit

Ardilla-Osorio

Penalvia

et al. 2020

Cells

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“…It has been calculated that autophagy controls the destiny of up to fifty per cent of the cellular proteins ( 24 ), and up to four percent of the mitochondria pool is basally degraded by mitophagy every day, while dysfunctional mitochondria are actively and selectively removed on demand ( 25 ). Thus, overall autophagy presides to protein and organelle quality control that preserves cell viability and prevents from cancer ( 26 , 27 ). Additional tumor suppressive mechanisms of autophagy include the elimination of oncogenic substrates and dampening of oxidative stress and inflammation, which contribute to preserve genome stability ( 28 , 29 ).…”

Section: Autophagy and Ovarian Cancermentioning

confidence: 99%

How Autophagy Shapes the Tumor Microenvironment in Ovarian Cancer

et al. 2020

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Ovarian cancer (OC) is characterized by a high mortality rate due to the late diagnosis and the elevated metastatic potential. Autophagy, a lysosomal-driven catabolic process, contributes to the macromolecular turnover, cell homeostasis, and survival, and as such, it represents a pathway targetable for anti-cancer therapies. It is now recognized that the vascularization and the cellular composition of the tumor microenvironment influence the development and progression of OC by controlling the availability of nutrients, oxygen, growth factors, and inflammatory and immune-regulatory soluble factors that ultimately impinge on autophagy regulation in cancer cells. An increasing body of evidence indicates that OC carcinogenesis is associated, at least in the early stages, to insufficient autophagy. On the other hand, when the tumor is already established, autophagy activation provides a survival advantage to the cancer cells that face metabolic stress and protects from the macromolecules and organelles damages induced by chemo- and radiotherapy. Additionally, upregulation of autophagy may lead cancer cells to a non-proliferative dormant state that protects the cells from toxic injuries while preserving their stem-like properties. Further to complicate the picture, autophagy is deregulated also in stromal cells. Thus, changes in the tumor microenvironment reflect on the metabolic crosstalk between cancer and stromal cells impacting on their autophagy levels and, consequently, on cancer progression. Here, we present a brief overview of the role of autophagy in OC hallmarks, including tumor dormancy, chemoresistance, metastasis, and cell metabolism, with an emphasis on the bidirectional metabolic crosstalk between cancer cells and stromal cells in shaping the OC microenvironment.

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“…In early tumorigenesis, mitophagy maintains the metabolic demand of normal cells and suppresses tumorigenesis. In late tumor development, mitophagy enhances cell tolerance and improves tumor progression [ 63 ]. The loss of mitochondrial function by mutation or functional change in a variety of critical genes leads to the accumulation of impaired mitochondria and the inhibition of mitophagy, thus, the induction of tumorigenesis [ 64 ].…”

Section: The Bipolar Role Of Autophagy In Cancermentioning

confidence: 99%

The Dual Role of Autophagy in Cancer Development and a Therapeutic Strategy for Cancer by Targeting Autophagy

Yun¹,

Jeon²,

et al. 2020

IJMS

116

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Autophagy is a delicate intracellular degradation process that occurs due to diverse stressful conditions, including the accumulation of damaged proteins and organelles as well as nutrient deprivation. The mechanism of autophagy is initiated by the creation of autophagosomes, which capture and encapsulate abnormal components. Afterward, autophagosomes assemble with lysosomes to recycle or remove degradative cargo. The regulation of autophagy has bipolar roles in cancer suppression and promotion in diverse cancers. Furthermore, autophagy modulates the features of tumorigenesis, cancer metastasis, cancer stem cells, and drug resistance against anticancer agents. Some autophagy regulators are used to modulate autophagy for anticancer therapy but the dual roles of autophagy limit their application in anticancer therapy, and present as the main reason for therapy failure. In this review, we summarize the mechanisms of autophagy, tumorigenesis, metastasis, cancer stem cells, and resistance against anticancer agents. Finally, we discuss whether targeting autophagy is a promising and effective therapeutic strategy in anticancer therapy.

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The Role of Mitochondrial Dynamics and Mitophagy in Carcinogenesis, Metastasis and Therapy

Cited by 97 publications

References 136 publications

Tafazzin Mutation Affecting Cardiolipin Leads to Increased Mitochondrial Superoxide Anions and Mitophagy Inhibition in Barth Syndrome

Tafazzin Mutation Affecting Cardiolipin Leads to Increased Mitochondrial Superoxide Anions and Mitophagy Inhibition in Barth Syndrome

How Autophagy Shapes the Tumor Microenvironment in Ovarian Cancer

The Dual Role of Autophagy in Cancer Development and a Therapeutic Strategy for Cancer by Targeting Autophagy

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