A dividing matter: Drp1/Dnm1-independent mitophagy

Graef, Martin

doi:10.1083/jcb.201611079

Cited by 16 publications

(12 citation statements)

References 18 publications

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“…Although Drp1 has been reported to be required for mammalian mitophagy, there is mixed evidence on this issue ( Graef, 2016 ). To assess whether mitochondrial fission is required for ΔOTC clearance, we overexpressed a dominant-negative mutant of Drp1 in the ΔOTC-inducible cell line and found that Drp1K38A expression did not inhibit ΔOTC clearance (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial fission facilitates the selective mitophagy of protein aggregates

Burman

Pickles

Wang

et al. 2017

Journal of Cell Biology

376

306

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Section: Resultsmentioning

confidence: 99%

Mitochondrial fission facilitates the selective mitophagy of protein aggregates

Burman

Pickles

Wang

et al. 2017

Journal of Cell Biology

376

306

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show abstract

“…Whether mitophagy requires prior Drp1-mediated mitochondrial fragmentation is still controversial. 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.…”

Section: Discussionmentioning

confidence: 99%

“…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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“…Despite evidence that fission regulates mitophagy 10 , 15 , the concept that Drp1 plays a direct mechanistic role in regulating mitophagy is controversial 71 . Evidence obtained in yeast 72 and mammalian cells 10 suggest that Drp1 (and Dnm1, the yeast homolog) is required for mitophagy while, in contrast, others have reported that Drp1 KO had no effect on mitophagy 73 or hypoxia-induced upregulation of mitophagy 74 , but may protect mitochondria from PINK/Parkin-mediated “wholesale mitophagy” 11 .…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial fission and mitophagy are independent mechanisms regulating ischemia/reperfusion injury in primary neurons

et al. 2021

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Mitochondrial dynamics and mitophagy are constitutive and complex systems that ensure a healthy mitochondrial network through the segregation and subsequent degradation of damaged mitochondria. Disruption of these systems can lead to mitochondrial dysfunction and has been established as a central mechanism of ischemia/reperfusion (I/R) injury. Emerging evidence suggests that mitochondrial dynamics and mitophagy are integrated systems; however, the role of this relationship in the context of I/R injury remains unclear. To investigate this concept, we utilized primary cortical neurons isolated from the novel dual-reporter mitochondrial quality control knockin mice (C57BL/6-Gt(ROSA)26Sortm1(CAG-mCherry/GFP)Ganl/J) with conditional knockout (KO) of Drp1 to investigate changes in mitochondrial dynamics and mitophagic flux during in vitro I/R injury. Mitochondrial dynamics was quantitatively measured in an unbiased manner using a machine learning mitochondrial morphology classification system, which consisted of four different classifications: network, unbranched, swollen, and punctate. Evaluation of mitochondrial morphology and mitophagic flux in primary neurons exposed to oxygen-glucose deprivation (OGD) and reoxygenation (OGD/R) revealed extensive mitochondrial fragmentation and swelling, together with a significant upregulation in mitophagic flux. Furthermore, the primary morphology of mitochondria undergoing mitophagy was classified as punctate. Colocalization using immunofluorescence as well as western blot analysis revealed that the PINK1/Parkin pathway of mitophagy was activated following OGD/R. Conditional KO of Drp1 prevented mitochondrial fragmentation and swelling following OGD/R but did not alter mitophagic flux. These data provide novel evidence that Drp1 plays a causal role in the progression of I/R injury, but mitophagy does not require Drp1-mediated mitochondrial fission.

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A dividing matter: Drp1/Dnm1-independent mitophagy

Abstract: Martin Graef highlights Yamashita et al.’s finding that mitophagy can occur independently of the canonical mitochondrial fission apparatus.

Cited by 16 publications

References 18 publications

Mitochondrial fission facilitates the selective mitophagy of protein aggregates

Mitochondrial fission facilitates the selective mitophagy of protein aggregates

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

Mitochondrial fission and mitophagy are independent mechanisms regulating ischemia/reperfusion injury in primary neurons

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