Cyclophilin D in mitochondrial pathophysiology

Giorgio, Valentina; Soriano, María Eugenia; Basso, Emy; Bisetto, Elena; Lippe, Giovanna; Forte, Michael; Bernardi, Paolo

doi:10.1016/j.bbabio.2009.12.006

Cited by 165 publications

(135 citation statements)

References 98 publications

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“…5B), which may act to confer antioxidant protection. Despite increased mitochondrial mitochondrial cyclophylin D (or F, as it is also described (Di Lisa et al, 2011, Giorgio et al, 2010) content is often associated with increased induction of the mPTP (Halestrap, 2010), since this was Fig. 3E), which may be related with the initial stages of cell death (Zorov et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial disruption occurs downstream from β-adrenergic overactivation by isoproterenol in differentiated, but not undifferentiated H9c2 cardiomyoblasts: Differential activation of stress and survival pathways

Branco

Sampaio

Wieckowski

et al. 2013

The International Journal of Biochemistry & Cell Biology

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Section: Discussionmentioning

confidence: 99%

Mitochondrial disruption occurs downstream from β-adrenergic overactivation by isoproterenol in differentiated, but not undifferentiated H9c2 cardiomyoblasts: Differential activation of stress and survival pathways

Branco

Sampaio

Wieckowski

et al. 2013

The International Journal of Biochemistry & Cell Biology

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“…Inhibition of cyclophilin D is thought to decrease the probability of pore opening. 13 Importantly, inhibition of SIRT3 activity by treating cells with ethanol enhanced the sensitivity of mitochondria to induction of MPT by increasing cyclophilin D activity. 14 By contrast, it has also been reported that in some instances cyclophilin D prevents apoptotic cell death through modulation of Bcl-2 and by promoting the binding of HKII to the mitochondria.…”

mentioning

confidence: 99%

SIRT3 protects from hypoxia and staurosporine-mediated cell death by maintaining mitochondrial membrane potential and intracellular pH

et al. 2012

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Mitochondrial sirtuin 3 (SIRT3) mediates cellular resistance toward various forms of stress. Here, we show that in mammalian cells subjected to hypoxia and staurosporine treatment SIRT3 prevents loss of mitochondrial membrane potential (DW mt ), intracellular acidification and reactive oxygen species accumulation. Our results indicate that: (i) SIRT3 inhibits mitochondrial permeability transition and loss of membrane potential by preventing HKII binding to the mitochondria, (ii) SIRT3 increases catalytic activity of the mitochondrial carbonic anhydrase VB, thereby preventing intracellular acidification, Bax activation and apoptotic cell death. In conclusion we propose that, in mammalian cells, SIRT3 has a central role in connecting changes in DW mt , intracellular pH and mitochondrial-regulated apoptotic pathways. Cell Death and Differentiation (2012) 19, 1815-1825 doi:10.1038/cdd.2012 published online 18 May 2012 Sirtuins are a family of protein highly conserved in both prokaryotes and eukaryotes. 1 The name derives from the Saccharomyces cerevisiae gene silent information regulator 2 (Sir2), the first known sirtuin, that, by silencing chromatin via deacetylation of histones, regulates both replicative and overall life span. 2 In mammals, seven Sir2 homologs, designated SIRT1 through SIRT7 have been identified, that regulate a wide range of intracellular processes including metabolism, longevity, aging, cancer and response to stress. 3-5 These proteins are characterized by an evolutionarily conserved sirtuin core domain 6 that contains the catalytic and nicotinamide adenine dinucleotide (NAD þ )-binding domain. Each sirtuin catalyzes protein deacetylation or adenosine diphosphate (ADP) ribosylation in vitro, requires NAD þ for enzymatic activity and generates nicotinamide, which then acts as a negative feedback inhibitor. 7 Because of the NAD þ requirement, sirtuins are categorized as class III histone deacetylases. 8 Mammalian sirtuins show distinct acetylated protein substrates and are localized in distinct subcellular compartments. Sirtuin 1 (SIRT1), SIRT6 and SIRT7 are in the nucleus, SIRT2 is primarily cytosolic and SIRT3, SIRT4 and SIRT5 are in the mitochondria. 9 Mitochondrial sirtuins participate in the regulation of ATP production, metabolism, apoptosis and cell signaling. 10 Among the three mitochondrial sirtuins, SIRT3 controls the global lysine acetylation of these organelles. 11 SIRT3 mediates cellular resistance toward various forms of stress by maintaining genomic stability and mitochondrial integrity. For example, SIRT3 influences cell survival by regulating the state of the mitochondrial permeability transition (MPT). However, the precise effects of SIRT3 on MPT are still not clear. In fact, some reports have shown that SIRT3 would deacetylate and inhibit the enzymatic activity of cyclophilin D 12 with the following dissociation from adenine nucleotide translocator, which, in turn, promotes detachment of hexokinase II (HKII) from voltage-dependent anion channel. Inhibition of cyclophilin D i...

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“…Ever since, the contribution of cypD in a variety of diseases has been strongly suggested or proven (for review, see Ref. 5), a momentum that was assisted by the wide availability of cypD knock-out (KO) mice. These studies converged to the conclusion that cypD-mediated mitochondrial permeability transition pore (PTP) regulates some forms of necrotic, but not apoptotic death.…”

mentioning

confidence: 99%

Complex Contribution of Cyclophilin D to Ca2+-induced Permeability Transition in Brain Mitochondria, with Relation to the Bioenergetic State

Dóczi

Turiák

Vajda

et al. 2011

Journal of Biological Chemistry

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Cyclophilin D (cypD)-deficient mice exhibit resistance to focal cerebral ischemia and to necrotic but not apoptotic stimuli. To address this disparity, we investigated isolated brain and in situ neuronal and astrocytic mitochondria from cypDdeficient and wild-type mice. Isolated mitochondria were challenged by high Ca 2؉ , and the effects of substrates and respiratory chain inhibitors were evaluated on permeability transition pore opening by light scatter. In situ neuronal and astrocytic mitochondria were visualized by mito-DsRed2 targeting and challenged by calcimycin, and the effects of glucose, NaCN, and an uncoupler were evaluated by measuring mitochondrial volume. In isolated mitochondria, Ca 2؉ caused a large cypDdependent change in light scatter in the absence of substrates that was insensitive to Ruthenium red or Ru360. Uniporter inhibitors only partially affected the entry of free Ca 2؉ in the matrix. Inhibition of complex III/IV negated the effect of substrates, but inhibition of complex I was protective. Mitochondria within neurons and astrocytes exhibited cypD-independent swelling that was dramatically hastened when NaCN and 2-deoxyglucose were present in a glucose-free medium during calcimycin treatment. In the presence of an uncoupler, cypD-deficient astrocytic mitochondria performed better than wild-type mitochondria, whereas the opposite was observed in neurons. Neuronal mitochondria were examined further during glutamate-induced delayed Ca 2؉ deregulation. CypD-knock-out mitochondria exhibited an absence or a delay in the onset of mitochondrial swelling after glutamate application. Apparently, some conditions involving deenergization render cypD an important modulator of PTP in the brain. These findings could explain why absence of cypD protects against necrotic (deenergized mitochondria), but not apoptotic (energized mitochondria) stimuli.

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Cyclophilin D in mitochondrial pathophysiology

Cited by 165 publications

References 98 publications

Mitochondrial disruption occurs downstream from β-adrenergic overactivation by isoproterenol in differentiated, but not undifferentiated H9c2 cardiomyoblasts: Differential activation of stress and survival pathways

Mitochondrial disruption occurs downstream from β-adrenergic overactivation by isoproterenol in differentiated, but not undifferentiated H9c2 cardiomyoblasts: Differential activation of stress and survival pathways

SIRT3 protects from hypoxia and staurosporine-mediated cell death by maintaining mitochondrial membrane potential and intracellular pH

Complex Contribution of Cyclophilin D to Ca2+-induced Permeability Transition in Brain Mitochondria, with Relation to the Bioenergetic State

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