Splitting up the powerhouse: structural insights into the mechanism of mitochondrial fission

Richter, Viviane; Singh, Abeer Prakash; Kvansakul, Marc; Ryan, Michael; Osellame, Laura D.

doi:10.1007/s00018-015-1950-y

Cited by 44 publications

(39 citation statements)

References 143 publications

(222 reference statements)

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“…The process begins with the translocation of Drp1 from the cytosol to the outer mitochondrial membrane where it interacts with various proteins, including Mff and Fis1, prior to cleavage plane formation. 33 Surprisingly, the most significant change in expression in SH-N-Myc cells was a 2.5-fold increase in the DRP1 transcript (Figure 3b, left). The MFF and FIS1 transcripts were also increased, albeit by >50% and did not rise to the level of significance.…”

Section: Resultsmentioning

confidence: 92%

N-Myc overexpression increases cisplatin resistance in neuroblastoma via deregulation of mitochondrial dynamics

Casinelli

LaRosa

Sharma

et al. 2016

Cell Death Discovery

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N-Myc is a global transcription factor that regulates the expression of genes involved in a number of essential cellular processes including: ribosome biogenesis, cell cycle and apoptosis. Upon deregulation, N-Myc can drive pathologic expression of many of these genes, which ultimately defines its oncogenic potential. Overexpression of N-Myc has been demonstrated to contribute to tumorigenesis, most notably for the pediatric tumor, neuroblastoma. Herein, we provide evidence that deregulated N-Myc alters the expression of proteins involved in mitochondrial dynamics. We found that N-Myc overexpression leads to increased fusion of the mitochondrial reticulum secondary to changes in protein expression due to aberrant transcriptional and post-translational regulation. We believe the structural changes in the mitochondrial network in response to N-Myc amplification in neuroblastoma contributes to two important aspects of tumor development and maintenance—bioenergetic alterations and apoptotic resistance. Specifically, we found that N-Myc overexpressing cells are resistant to programmed cell death in response to exposure to low doses of cisplatin, and demonstrated that this was dependent on increased mitochondrial fusion. We speculate that these changes in mitochondrial structure and function may contribute significantly to the aggressive clinical ph9enotype of N-Myc amplified neuroblastoma.

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Section: Resultsmentioning

confidence: 92%

N-Myc overexpression increases cisplatin resistance in neuroblastoma via deregulation of mitochondrial dynamics

Casinelli

LaRosa

Sharma

et al. 2016

Cell Death Discovery

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“…Biochemical and structural studies indicated that the mechanisms of DLP1‐induced mitochondrial fission were similar to those by other members of the dynamin‐superfamily (Richter et al ., 2015). DLP1 recruited to the outer membrane of mitochondria assembles into a ring structure, which induces the scission of mitochondria.…”

Section: Discussionmentioning

confidence: 99%

DLP1‐dependent mitochondrial fragmentation and redistribution mediate prion‐associated mitochondrial dysfunction and neuronal death

Wang

et al. 2017

Aging Cell

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SummaryMitochondrial malfunction is a universal and critical step in the pathogenesis of many neurodegenerative diseases including prion diseases. Dynamin‐like protein 1 (DLP1) is one of the key regulators of mitochondrial fission. In this study, we investigated the role of DLP1 in mitochondrial fragmentation and dysfunction in neurons using in vitro and in vivo prion disease models. Mitochondria became fragmented and redistributed from axons to soma, correlated with increased mitochondrial DLP1 expression in murine primary neurons (N2a cells) treated with the prion peptide PrP106–126 in vitro as well as in prion strain‐infected hamster brain in vivo. Suppression of DLP1 expression by DPL1 RNAi inhibited prion‐induced mitochondrial fragmentation and dysfunction (measured by ADP/ATP ratio, mitochondrial membrane potential, and mitochondrial integrity). We also demonstrated that DLP1 RNAi is neuroprotective against prion peptide in N2a cells as shown by improved cell viability and decreased apoptosis markers, caspase 3 induced by PrP106–126. On the contrary, overexpression of DLP1 exacerbated mitochondrial dysfunction and cell death. Moreover, inhibition of DLP1 expression ameliorated PrP106–126‐induced neurite loss and synaptic abnormalities (i.e., loss of dendritic spine and PSD‐95, a postsynaptic scaffolding protein as a marker of synaptic plasticity) in primary neurons, suggesting that altered DLP1 expression and mitochondrial fragmentation are upstream events that mediate PrP106–126‐induced neuron loss and degeneration. Our findings suggest that DLP1‐dependent mitochondrial fragmentation and redistribution plays a pivotal role in PrPS c‐associated mitochondria dysfunction and neuron apoptosis. Inhibition of DLP1 may be a novel and effective strategy in the prevention and treatment of prion diseases.

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“…At the mitochondria, Drp1 oligomerizes into higher-order spirals, which triggers GTP hydrolysis and subsequent constriction of the mitochondria [4,37]. Drp1-driven constriction is sufficient to narrow the mitochondrial diameter but insufficient to promote its complete severing [37,38]. Recently, Lee et al demonstrated that dynamin-2 is recruited to sites of Drp1-mediated constriction and severs the mitochondria to complete mitochondrial fission [39].…”

Section: Mitochondrial Dynamics Machinerymentioning

confidence: 99%

The Interplay between Oncogenic Signaling Networks and Mitochondrial Dynamics

Nagdas

Kashatus

2017

Antioxidants

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Mitochondria are dynamic organelles that alter their organization in response to a variety of cellular cues. Mitochondria are central in many biologic processes, such as cellular bioenergetics and apoptosis, and mitochondrial network morphology can contribute to those physiologic processes. Some of the biologic processes that are in part governed by mitochondria are also commonly deregulated in cancers. Furthermore, patient tumor samples from a variety of cancers have revealed that mitochondrial dynamics machinery may be deregulated in tumors. In this review, we will discuss how commonly mutated oncogenes and their downstream effector pathways regulate the mitochondrial dynamics machinery to promote changes in mitochondrial morphology as well as the physiologic consequences of altered mitochondrial morphology for tumorigenic growth.

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Splitting up the powerhouse: structural insights into the mechanism of mitochondrial fission

Cited by 44 publications

References 143 publications

N-Myc overexpression increases cisplatin resistance in neuroblastoma via deregulation of mitochondrial dynamics

N-Myc overexpression increases cisplatin resistance in neuroblastoma via deregulation of mitochondrial dynamics

DLP1‐dependent mitochondrial fragmentation and redistribution mediate prion‐associated mitochondrial dysfunction and neuronal death

The Interplay between Oncogenic Signaling Networks and Mitochondrial Dynamics

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