Mitochondrial division occurs concurrently with autophagosome formation but independently of Drp1 during mitophagy

Yamashita, Shun ichi; Jin, Xiulian; Furukawa, Kentaro; Hamasaki, Maho; Nezu, Akihiro; Otera, Hidenori; Saigusa, Toyohei; Yoshimori, Tamotsu; Sakai, Yasuyoshi; Mihara, Katsuyoshi; Kanki, Tomotake

doi:10.1083/jcb.201605093

Cited by 175 publications

(172 citation statements)

References 58 publications

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“…62 For instance, mitochondrial division during mitophagy can occur in a Drp1-independent manner. 63 On the other hand, Drp1-dependent mitochondrial fragmentation might facilitate mitophagy by creating small-size fragments facilitating autophagosomal uptake. 62 …”

Section: Discussionmentioning

confidence: 99%

Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells

et al. 2017

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Inhibition of complex I (CI) of the mitochondrial respiratory chain by BAY 87-2243 ('BAY') triggers death of BRAF V600E melanoma cell lines and inhibits in vivo tumor growth. Here we studied the mechanism by which this inhibition induces melanoma cell death. BAY treatment depolarized the mitochondrial membrane potential (Δψ), increased cellular ROS levels, stimulated lipid peroxidation and reduced glutathione levels. These effects were paralleled by increased opening of the mitochondrial permeability transition pore (mPTP) and stimulation of autophagosome formation and mitophagy. BAY-induced cell death was not due to glucose shortage and inhibited by the antioxidant α-tocopherol and the mPTP inhibitor cyclosporin A. Tumor necrosis factor receptor-associated protein 1 (TRAP1) overexpression in BAY-treated cells lowered ROS levels and inhibited mPTP opening and cell death, whereas the latter was potentiated by TRAP1 knockdown. Knockdown of autophagy-related 5 (ATG5) inhibited the BAY-stimulated autophagosome formation, cellular ROS increase and cell death. Knockdown of phosphatase and tensin homologinduced putative kinase 1 (PINK1) inhibited the BAY-induced Δψ depolarization, mitophagy stimulation, ROS increase and cell death. Dynamin-related protein 1 (Drp1) knockdown induced mitochondrial filamentation and inhibited BAY-induced cell death. The latter was insensitive to the pancaspase inhibitor z-VAD-FMK, but reduced by necroptosis inhibitors (necrostatin-1, necrostatin-1s)) and knockdown of key necroptosis proteins (receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and mixed lineage kinase domain-like (MLKL)). BAY-induced cell death was also reduced by the ferroptosis inhibitor ferrostatin-1 and overexpression of the ferroptosis-inhibiting protein glutathione peroxidase 4 (GPX4). This overexpression also inhibited the BAYinduced ROS increase and lipid peroxidation. Conversely, GPX4 knockdown potentiated BAY-induced cell death. We propose a chain of events in which: (i) CI inhibition induces mPTP opening and Δψ depolarization, that (ii) stimulate autophagosome formation, mitophagy and an associated ROS increase, leading to (iii) activation of combined necroptotic/ferroptotic cell death.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells

et al. 2017

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“…Molecular replacement strategies maintain the whole organelle by replacement of parts, perhaps analogous to the restoration of historic buildings. This third catchall category may involve the degradation and replacement of individual proteins, protein complexes or possibly the export of material destined for degradation through mitochondria-derived transport vesicles that pinch off from mitochondria independently of fission machinery or canonical autophagy machinery (McLelland et al, 2016; Soubannier et al, 2012; Sugiura et al, 2014), or by extraction directly from the tubular sides of mitochondria by attacking autophagosomes (Yamashita et al, 2016). Although several have estimated that at basal rates, cultured cells produce 50 autophagosomes per hour, it is currently not known what volume of mitochondrial biomass is turned over by any of these processes in neurons or other cell types, nor whether all of the different processes work in concert.…”

Section: Mitochondrial Turnovermentioning

confidence: 99%

Section: Mitochondrial Turnovermentioning

confidence: 99%

“…However, more recent work identified a Drp1/Dnm1-independent mitophagy process conserved in yeast and mammals (Yamashita et al, 2016). In this case, distinct from organelle fission, small fragments of mitochondria are generated in the absence of Drp1/Dnm1 because they are apparently extracted from the sides of mitochondrial tubules by attacking autophagosomes (Yamashita et al, 2016). In this case, the autophagosome itself appears to form at spots along mitochondria with or without Drp1/Dnm1 to consume a bulge along the mitochondrial tubule (Yamashita et al, 2016) (see section 7.4 ).…”

Section: Mitochondrial Turnovermentioning

confidence: 99%

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Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

Aouacheria

Baghdiguian

Lamb

et al. 2017

Neurochemistry International

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The morphology of a population of mitochondria is the result of several interacting dynamical phenomena, including fission, fusion, movement, elimination and biogenesis. Each of these phenomena is controlled by underlying molecular machinery, and when defective can cause disease. New understanding of the relationships between form and function of mitochondria in health and disease is beginning to be unraveled on several fronts. Studies in mammals and model organisms have revealed that mitochondrial morphology, dynamics and function appear to be subject to regulation by the same proteins that regulate apoptotic cell death. One protein family that influences mitochondrial dynamics in both healthy and dying cells is the Bcl-2 protein family. Connecting mitochondrial dynamics with life-death pathway forks may arise from the intersection of Bcl-2 family proteins with the proteins and lipids that determine mitochondrial shape and function. Bcl-2 family proteins also have multifaceted influences on cells and mitochondria, including calcium handling, autophagy and energetics, as well as the subcellular localization of mitochondrial organelles to neuronal synapses. The remarkable range of physical or functional interactions by Bcl-2 family proteins is challenging to assimilate into a cohesive understanding. Most of their effects may be distinct from their direct roles in apoptotic cell death and are particularly apparent in the nervous system. Dual roles in mitochondrial dynamics and cell death extend beyond BCL-2 family proteins. In this review, we discuss many processes that govern mitochondrial structure and function in health and disease, and how Bcl-2 family proteins integrate into some of these processes.

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“…Recent work suggests mDivi1 does not target Drp1 and instead functions as a mitochondrial complex I inhibitor . Additionally, there is mounting evidence for Drp1‐independent mitophagy . Remarkably, research from the Dorn laboratory revealed that mitophagy is actually promoted in the absence of Drp1 and inhibited in the absence of the fusion proteins Mfn1 and Mfn2 .…”

Section: Mechanistic Basics For Mitophagy Initiationmentioning

confidence: 99%

Mammalian mitophagy – from in vitro molecules to in vivo models

2017

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The autophagic turnover of mitochondria, termed mitophagy, is thought to play an essential role in not only maintaining the health of the mitochondrial network but also that of the cell and organism as a whole. We have come a long way in identifying the molecular components required for mitophagy through extensive in vitro work and cell line characterisation, yet the physiological significance and context of these pathways remain largely unexplored. This is highlighted by the recent development of new mouse models that have revealed a striking level of variation in mitophagy, even under normal conditions. Here, we focus on programmed mitophagy and summarise our current understanding of why, how and where this takes place in mammals.

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Mitochondrial division occurs concurrently with autophagosome formation but independently of Drp1 during mitophagy

Abstract: It remains controversial whether Dnm1/Drp1-mediated mitochondrial division is essential for mitophagy. Yamashita et al. show that Dnm1/Drp1-independent mitochondrial division occurs after formation of isolation membranes and in cooperation with autophagosome formation during mitophagy.

Cited by 175 publications

References 58 publications

Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells

Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

Mammalian mitophagy – from in vitro molecules to in vivo models

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