Mitophagy Plays an Essential Role in Reducing Mitochondrial Production of Reactive Oxygen Species and Mutation of Mitochondrial DNA by Maintaining Mitochondrial Quantity and Quality in Yeast

Kurihara, Yusuke; Kanki, Tomotake; Aoki, Yoshimasa; Hirota, Yuko; Saigusa, Toyohei; Uchiumi, Takeshi; Kang, Dongchon

doi:10.1074/jbc.m111.280156

Cited by 236 publications

(195 citation statements)

References 31 publications

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“…Besides apoptosis, HDAC5 depletion also induces an autophagic programme called mitophagy, a 'selfeating' process whereby ROS-producing mitochondria are eliminated. 23 This mechanism would help cells to survive as inhibition of HDAC5 silencing-dependent autophagy accelerates apoptosis, supporting the rationale for further testing autophagy inhibitors in conjunction with HDAC5 inhibition as a new combined therapy as already reported for broad-spectrum HDACi. 24,25 Modulation of VUDP-1/TBP2/thioredoxin expression, which consequently increases intracellular ROS, has been proposed as one of the mechanisms underlying HDACi-induced cell death.…”

Section: Discussionsupporting

confidence: 56%

Metabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition

et al. 2017

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The US FDA approval of broad-spectrum histone deacetylase (HDAC) inhibitors has firmly laid the cancer community to explore HDAC inhibition as a therapeutic approach for cancer treatment. Hitting one HDAC member could yield clinical benefit but this required a complete understanding of the functions of the different HDAC members. Here we explored the consequences of specific HDAC5 inhibition in cancer cells. We demonstrated that HDAC5 inhibition induces an iron-dependent reactive oxygen species (ROS) production, ultimately leading to apoptotic cell death as well as mechanisms of mitochondria quality control (mitophagy and mitobiogenesis). Interestingly, adaptation of HDAC5-depleted cells to oxidative stress passes through reprogramming of metabolic pathways towards glucose and glutamine. Therefore, interference with both glucose and glutamine supply in HDAC5-inhibited cancer cells significantly increases apoptotic cell death and reduces tumour growth in vivo; providing insight into a valuable clinical strategy combining the selective inhibition of HDAC5 with various inhibitors of metabolism as a new therapy to kill cancer cells.

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Section: Discussionsupporting

confidence: 56%

Metabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition

et al. 2017

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“…Defective removal of damaged mitochondria could lead to increased ROS amounts with consequent accumulation of mutations in mitochondrial and nuclear DNA, thus favouring cancer onset. Mitophagy has been implicated in the removal of damaged mitochondria containing high levels of ROS [136,137] and ROS accumulation can promote by itself mitophagy activation, for example through mitochondrial membrane depolarization and Parkin/PINK1 pathway activation [138,139], thereby inhibiting initial tumor growth. Indeed, Parkin deficient mice spontaneously develop hepatic tumors [140], and PINK1 mutations have been described in neuroblastoma [141].…”

Section: Mitochondrial Dynamics and Mitophagy In Cancermentioning

confidence: 99%

The mitochondrial dynamics in cancer and immune-surveillance

Simula

Nazio

Campello

2017

Seminars in Cancer Biology

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A B S T R A C TMitochondria-shaping proteins control the dynamic equilibrium between fusion and fission of the mitochondrial network. Their balance is strictly required to regulate various processes, including the quality of mitochondria, cell metabolism, cell death, proliferation and cell migration. Alterations in these processes are frequently encountered in cancer, during both its onset and later progression, as evidence emerge connecting alterations in mitochondrial dynamics with cancer development. In recent years, novel therapeutic approaches to fight against different human tumors aim at exploiting the immune system's ability to specifically recognize tumor antigens, thus killing malignant cells in a process named immune-surveillance. Interestingly, data are accumulating on the role that mitochondrial dynamics play also for the correct function of both the innate and the adaptive immune system. By this review, we overview how mitochondrial dynamics can affect various processes during cancer development, acting directly on tumor cells or indirectly on cells responsible for tumor aggression and defence.

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“…Subsequently, we tested whether the protective effect of MB against ACI injury was altered after mitophagy was inhibited. Given that ROS are recognized as central mediators of neuroinflammation and cytotoxicity caused by ischemia and that mitophagy blocks the generation of ROS (24,46), we examined the ROS levels after mitophagy was inhibited. We found that OGD caused an elevation of ROS and that MB suppressed this elevation of ROS.…”

Section: Mitophagy Mediates the Protection Of Mb Against Acute Ischemmentioning

confidence: 99%

“…In this process, damaged mitochondria are enveloped by double-membrane structures known as autophagosomes, which are then delivered to lysosomes for degradation (21)(22)(23). Thus, mitophagy plays a crucial role in controlling the quality of mitochondria by preventing the generation of ROS by dysfunctional mitochondria (24,25). Deficiency in mitophagy is associated with neurodegenerative diseases such as Parkinson's disease (26,27), Alzheimer's disease (28,29) and Huntington's disease (30).…”

Section: Introductionmentioning

confidence: 99%