Tight control of mitochondrial membrane potential by cytochrome c oxidase

Pacelli, Consiglia; Latorre, Daniela; Cocco, Tiziana; Capuano, Ferdinando; Kukat, Christian; Seibel, Peter; Villani, Gaetano

doi:10.1016/j.mito.2010.12.004

Cited by 45 publications

(33 citation statements)

References 35 publications

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“…COX is the terminal, proposed rate-limiting enzyme of the electron transport chain (ETC) 55, 56 . COX, with other ETC complexes, generates the ΔΨ m which is required for increased ATP synthesis, but also increased mitochondrial ROS.…”

Section: Resultsmentioning

confidence: 99%

Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency

et al. 2014

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Dysfunctional stem cell differentiation into placental lineages is associated with gestational diseases. Of the differentiated lineages available to trophoblast stem cells (TSC), elevated O2 and mitochondrial function are necessary to placental lineages at the maternal-placental surface and important in the etiology of preeclampsia. TSC lineage imbalance leads to embryonic failure during uterine implantation. Stress at implantation exacerbates stem cell depletion by decreasing proliferation and increasing differentiation. Implantation site O2 is normally ~2%. In culture, exposure to 2% O2 and fibroblast growth factor (FGF)4 enabled highest mouse TSC multipotency and proliferation. In contrast, hypoxic stress (0.5% O2) initiated the most TSC differentiation after 24 hr despite FGF4. However, hypoxic stress supported differentiation poorly after 4–7 days, despite FGF4 removal. At all tested O2 levels, FGF4 maintained Warburg metabolism; mitochondrial inactivity and aerobic glycolysis. However, hypoxic stress suppressed mitochondrial membrane potential, maintained low mitochondrial cytochrome c oxidase (oxidative phosphorylation/OxPhos), and high pyruvate kinase M2 (glycolysis) despite FGF4 removal. Inhibiting OxPhos inhibited differentiation at the differentiation optimum at 20% O2. Moreover, adding differentiation-inducing hyperosmolar stress failed to induce differentiation during hypoxia. Thus, differentiation depended on OxPhos at 20% O2; hypoxic and hyperosmolar stresses did not induce differentiation at 0.5% O2. Hypoxia-limited differentiation and mitochondrial inhibition and activation suggest that differentiation into two lineages of the labyrinthine placenta requires O2>0.5–2% and mitochondrial function. Stress-activated protein kinase increases an early lineage and suppresses later lineages in proportion to the deviation from optimal O2 for multipotency, thus it is the first enzyme reported to prioritize differentiation.

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Section: Resultsmentioning

confidence: 99%

Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency

et al. 2014

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“…The data suggest that the ability of these proteins to prevent cell death may be attributed to their ability to maintain mitochondrial homeostasis. CcOX, the terminal subunit of the mitochondrial respiratory chain, tightly controls ΔΨ m and is a target of ATN-224 (13,23,24). Here we show that ATN-224 treatment decreases ΔΨ m , independent of Bcl-2, Bcl-xL or Mcl-1 status, thus affecting their ability to maintain homeostasis.…”

Section: Discussionmentioning

confidence: 99%

The copper chelator ATN-224 induces caspase-independent cell death in diffuse large B cell lymphoma

Lee

Hart

Briehl

et al. 2014

International Journal of Oncology

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Bcl-2 and other anti-apoptotic proteins are associated with defective caspase-dependent apoptotic pathways, resulting in chemoresistance. We have previously shown that ATN-224, a copper chelator drug, induces cell death in murine thymic lymphoma cells transfected with Bcl-2. In the current study, we tested whether ATN-224 was effective in diffuse large B cell lymphoma (DLBCL) cells, which have increased anti-apoptotic proteins through translocation or amplification. We found that nanomolar concentrations of ATN-224 induced cell death in DLBCL cells independent of Bcl-2, Bcl-xL or Mcl-1 status. ATN-224 treatment resulted in mitochondrial dysfunction, release of apoptosis-inducing factor (AIF) and induction of caspase-independent cell death. In addition, ATN-224 degraded Mcl-1 and enhanced the effect of the BH3 mimetic ABT-263. These findings indicate that ATN-224 has potential as a therapeutic for the treatment of DLBCL. Induction of caspase-independent cell death in apoptosis-resistant DLBCL would provide a therapeutic alternative for the treatment of refractory disease.

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“…2006; Pacelli et al. 2011; Arnold 2012). Complex IV is the terminus of the respiratory chain of mitochondria, catalyzing the transfer of electrons from reduced cytochrome c to oxygen and in turn reducing oxygen to water.…”

Section: Speciation Via Mitonuclear Coevolution To Maintain Coadaptationmentioning

confidence: 99%

Mitonuclear coevolution as the genesis of speciation and the mitochondrial DNA barcode gap

Hill

2016

Ecology and Evolution

150

178

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Mitochondrial genes are widely used in taxonomy and systematics because high mutation rates lead to rapid sequence divergence and because such changes have long been assumed to be neutral with respect to function. In particular, the nucleotide sequence of the mitochondrial gene cytochrome c oxidase subunit 1 has been established as a highly effective DNA barcode for diagnosing the species boundaries of animals. Rarely considered in discussions of mitochondrial evolution in the context of systematics, speciation, or DNA barcodes, however, is the genomic architecture of the eukaryotes: Mitochondrial and nuclear genes must function in tight coordination to produce the complexes of the electron transport chain and enable cellular respiration. Coadaptation of these interacting gene products is essential for organism function. I extend the hypothesis that mitonuclear interactions are integral to the process of speciation. To maintain mitonuclear coadaptation, nuclear genes, which code for proteins in mitochondria that cofunction with the products of mitochondrial genes, must coevolve with rapidly changing mitochondrial genes. Mitonuclear coevolution in isolated populations leads to speciation because population‐specific mitonuclear coadaptations create between‐population mitonuclear incompatibilities and hence barriers to gene flow between populations. In addition, selection for adaptive divergence of products of mitochondrial genes, particularly in response to climate or altitude, can lead to rapid fixation of novel mitochondrial genotypes between populations and consequently to disruption in gene flow between populations as the initiating step in animal speciation. By this model, the defining characteristic of a metazoan species is a coadapted mitonuclear genotype that is incompatible with the coadapted mitochondrial and nuclear genotype of any other population.

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Tight control of mitochondrial membrane potential by cytochrome c oxidase

Cited by 45 publications

References 35 publications

Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency

Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency

The copper chelator ATN-224 induces caspase-independent cell death in diffuse large B cell lymphoma

Mitonuclear coevolution as the genesis of speciation and the mitochondrial DNA barcode gap

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