Preventing Mitochondrial Fission Impairs Mitochondrial Function and Leads to Loss of Mitochondrial DNA

Parone, Philippe A.; Cruz, Sandrine Da; Tondera, Daniel; Mattenberger, Yves Benoît; James, Dominic I.; Maechler, Pierre; Barja, François; Martinou, Jean‐Claude

doi:10.1371/journal.pone.0003257

Cited by 371 publications

(303 citation statements)

References 45 publications

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“…In line with this, Opa-1-driven cristae remodelling is strictly required for regulating ATP production upon different cell needs [84], while Mfn-2 overexpression in myotubes can upregulate the transcription of OXPHOS genes [85]. However, in HeLa cells, prolonged Drp1 downregulation can reduce respiration levels [86], this suggesting that optimal OXPHOS activity requires a balanced equilibrium in mitochondrial morphology. Very recently, even in induced pluripotent stem cells (iPS), the OXPHOS-to-glycolysis switch has been associated with increased mitochondrial fragmentation due to ERK-dependent Drp1 activation [87].…”

Section: Mitochondrial Dynamics and Cell Metabolismmentioning

confidence: 80%

“…On the other side, accumulation of mutated mtDNA copies into fragmented and dysfunctional organelles could promote their degradation through mitophagy (see below), with subsequent mitochondrial biogenesis to recreate a healthy network. Preventing Drp1-dependent sequestration of damaged organelles impairs mitophagy and leads to accumulation of damaged mitochondria, so decreasing respiration capacity and ATP production [105].…”

Section: Mitochondrial Dynamics and Cell Metabolismmentioning

confidence: 99%

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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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Section: Mitochondrial Dynamics and Cell Metabolismmentioning

confidence: 80%

Section: Mitochondrial Dynamics and Cell Metabolismmentioning

confidence: 99%

The mitochondrial dynamics in cancer and immune-surveillance

Simula

Nazio

Campello

2017

Seminars in Cancer Biology

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“…41,42 DRP1 deletion also results in impairment of respiratory function in mitochondria due to oxidative stress that can lead to further increases in the production of reactive oxygen species. 43,44 In cultured postnatal mouse cortical neurons, DRP1 overexpression enhances neuronal viability and restores a normal pattern of mitochondrial morphology following DNA damage. 45 Furthermore, DRP1 is required for a normal rate of cytochrome c release and caspase activation during apoptosis.…”

Section: Discussionmentioning

confidence: 99%

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

et al. 2014

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Although the aberrant activation of cell cycle proteins has a critical role in neuronal death, effectors or mediators of cyclin D1/ cyclin-dependent kinase 4 (CDK4)-mediated death signal are still unknown. Here, we describe a previously unsuspected role of LIM kinase 2 (LIMK2) in programmed necrotic neuronal death. Downregulation of p27 Kip1 expression by Rho kinase (ROCK) activation induced cyclin D1/CDK4 expression levels in neurons vulnerable to status epilepticus (SE). Cyclin D1/CDK4 complex subsequently increased LIMK2 expression independent of caspase-3 and receptor interacting protein kinase 1 activity. In turn, upregulated LIMK2 impaired dynamic-related protein-1 (DRP1)-mediated mitochondrial fission without alterations in cofilin phosphorylation/expression and finally resulted in necrotic neuronal death. Inhibition of LIMK2 expression and rescue of DRP1 function attenuated this programmed necrotic neuronal death induced by SE. Therefore, we suggest that the ROCK-p27 Kip1 -cyclin D1/CDK4-LIMK2-DRP1-mediated programmed necrosis may be new therapeutic targets for neuronal death. The cell cycle is essential for a vital process, including proliferation, differentiation and survival of various cells. Cell cycle progression is regulated by two classes of proteins, the cyclins and the cyclin-dependent kinases (CDKs). Among them, cyclin D1 forms a complex with CDK4 and inactivates retinoblastoma protein (Rb) through phosphorylation resulting in activating E2 promoter-binding factor (E2F) family of transcription factors. Active E2F induces various gene transcriptions involving the cell cycle. 1 In post-mitotic neurons, some pathological conditions upregulate cyclin D1/CDK4 complex expression to induce activation of E2F members that contributes to increased transcription of proapoptotic molecules. 2,3 However, it is unclear whether cyclin D1 expression directly induces neuronal death for a number of following reasons. First, due to a time lag between cyclin D1/CDK4 expression and the onset of DNA fragmentation, most cyclin D1-positive neurons show TUNEL negativity. 4,5 Second, cyclin D1 level is unaltered in cultured embryonic neurons following apoptosis induction. 6 Third, Rb phosphorylation is rarely observed in vivo, 4 although cyclin D1/CDK4 complex phosphorylates Rb protein in apoptotic cultured neurons. 6 Fourth, cyclin D1 induction following ischemia is associated with regeneration and resistance to apoptosis rather than a mediator of apoptosis. 5,7,8 Fifth, effectors or mediators of cyclin D1/CDK4-mediated death signal are still unknown. Finally, neuronal death induced by various insults is morphologically necrotic rather than apoptotic. 9-12 Therefore, it is likely that some essential factors are missing in the cyclin D/CDK4-mediated neuronal death pathway.LIM kinases (LIMK1 and LIMK2) phosphorylate cofilin that is a stimulus-responsive mediator of actin dynamics. [13][14][15] Interestingly, non-phosphorylated cofilin targets mitochondrial membranes in response to apoptotic stimuli for cytochrome c releas...

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“…For instance, Drp1 knockdown in HeLa cells led to increased oxidative damage and decreased respiratory activities while Drp1KO MEFs maintain normal respiration and ATP levels (Benard et al, 2007;Parone et al, 2008;Ishihara et al, 2009;Wakabayashi et al, 2009). ROS levels or the susceptibility to ROS may be different in these cells.…”

Section: Immunofluorescence Of Cerebellar Sectionsmentioning

confidence: 99%