Down-regulation of OPA1 alters mouse mitochondrial morphology, PTP function, and cardiac adaptation to pressure overload

Piquereau, Jérôme; Caffin, Fanny; Novotová, Marta; Prola, Alexandre; Garnier, Anne; Matéo, Philippe; Fortin, D.; Huynh, Le Ha; Nicolas, Valérie; Alavi, Marcel V.; Brenner, Catherine; Ventura‐Clapier, Renée; Veksler, Vladimir; Joubert, Frédéric

doi:10.1093/cvr/cvs117

Cited by 171 publications

(156 citation statements)

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“…Although our data in HeLa cells were partly at variance with those of Kushnareva et al [55] (in this respect see [56]), studies on the Ca 2+ retention capacity of mitochondria in OPA1-silenced murine retinal ganglion cells [16] and the Ca 2+ sensitivity of mitochondrial permeability transition pore in OPA1-silenced HeLa cells [55] are in harmony with our observations. The report that knock-down of Opa1 increased the amplitude of Ca 2+ uptake and the Ca 2+ retention capacity in murine cardiac mitochondria [57] also supports the conclusion that an impairment of OPA1 function may lead to enhanced mitochondrial Ca 2+ signalling.…”

Section: Discussionsupporting

confidence: 69%

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Fülöp¹,

Rajki²,

Maka³

et al. 2015

Cell Calcium

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The most frequent form of hereditary blindness, Autosomal Dominant Optic Atrophy (ADOA) is caused by the mutation of the mitochondrial protein Opa1 and the ensuing degeneration of retinal ganglion cells. Previously we found that knockdown of OPA1 enhanced mitochondrial Ca 2+ uptake (Fülöp et al.,PLoS One 2011). Therefore we studied mitochondrial Ca 2+ metabolism in fibroblasts obtained from members of an ADOA family. Gene sequencing revealed heterozygosity for a splice site mutation (c. 984+1G>A) in intron 9 of the OPA1 gene. ADOA cells showed a higher rate of apoptosis than control cells and their mitochondria displayed increased fragmentation when forced to oxidative metabolism. The ophthalmological parameters critical fusion frequency and ganglion cell -inner plexiform layer thickness were inversely correlated to the evoked mitochondrial Ca 2+ signals. The present data indicate that enhanced mitochondrial Ca 2+ uptake is a pathogenetic factor in the progress of ADOA.3

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Section: Discussionsupporting

confidence: 69%

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Fülöp¹,

Rajki²,

Maka³

et al. 2015

Cell Calcium

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“…Fourth, the Opa1 reduction greatly mimicked the phenotypes caused by Tom70 deficiency ( Figure 6). Finally, Opa1 reduction tightly links to the chronic pressure overload-induced cardiac hypertrophy and the concurrently fragmented and swollen mitochondria [24]. Additionally, it has been described that an increase in the short cytoplasmic fragments of Opa1 links to cell apoptosis [25].…”

Section: Discussionmentioning

confidence: 97%

Tom70 serves as a molecular switch to determine pathological cardiac hypertrophy

Liu

et al. 2014

Cell Res

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Pathological cardiac hypertrophy is an inevitable forerunner of heart failure. Regardless of the etiology of cardiac hypertrophy, cardiomyocyte mitochondrial alterations are always observed in this context. The translocases of mitochondrial outer membrane (Tom) complex governs the import of mitochondrial precursor proteins to maintain mitochondrial function under pathophysiological conditions; however, its role in the development of pathological cardiac hypertrophy remains unclear. Here, we showed that Tom70 was downregulated in pathological hypertrophic hearts from humans and experimental animals. The reduction in Tom70 expression produced distinct pathological cardiomyocyte hypertrophy both in vivo and in vitro. The defective mitochondrial import of Tom70-targeted optic atrophy-1 triggered intracellular oxidative stress, which led to a pathological cellular response. Importantly, increased Tom70 levels provided cardiomyocytes with full resistance to diverse pro-hypertrophic insults. Together, these results reveal that Tom70 acts as a molecular switch that orchestrates hypertrophic stresses and mitochondrial responses to determine pathological cardiac hypertrophy. Keywords: pathological cardiac hypertrophy; translocases of mitochondrial outer membrane; optic atrophy-1; oxidative stress Cell Research (2014) 24:977-993.

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“…Recent studies also suggest that the fusion proteins (180) 4-HNE, 4-hydroxynonenal; CAT, catalase; GPX, glutathione peroxidase; GSH, glutathione; IFM, intermyofibrillar mitochondria; LC3, light chain 3; mCAT, catalase targeted to the mitochondrial matrix; MDA, malondialdehyde; MnSOD, manganese-dependent superoxide dismutase; PolG, mtDNA polymerase-␥; SSM, subsarcolemmal mitochondria; Tg-Sirt1, Sirt1 transgenic; WT, wild-type. OPA1, Mfn1, and Mfn2 are required to maintain normal mitochondrial function and prevent the development of cardiac hypertrophy and heart failure (24,150,151,156).…”

Section: Role Of Mitochondrial Dynamics In Cardiovascular Phys-mentioning

confidence: 99%

Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

Marzetti

Csiszár

Dutta

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

175

131

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Advanced age is associated with a disproportionate prevalence of cardiovascular disease (CVD). Intrinsic alterations in the heart and the vasculature occurring over the life course render the cardiovascular system more vulnerable to various stressors in late life, ultimately favoring the development of CVD. Several lines of evidence indicate mitochondrial dysfunction as a major contributor to cardiovascular senescence. Besides being less bioenergetically efficient, damaged mitochondria also produce increased amounts of reactive oxygen species, with detrimental structural and functional consequences for the cardiovascular system. The agerelated accumulation of dysfunctional mitochondrial likely results from the combination of impaired clearance of damaged organelles by autophagy and inadequate replenishment of the cellular mitochondrial pool by mitochondriogenesis. In this review, we summarize the current knowledge about relevant mechanisms and consequences of age-related mitochondrial decay and alterations in mitochondrial quality control in the cardiovascular system. The involvement of mitochondrial dysfunction in the pathogenesis of cardiovascular conditions especially prevalent in late life and the emerging connections with neurodegeneration are also illustrated. Special emphasis is placed on recent discoveries on the role played by alterations in mitochondrial dynamics (fusion and fission), mitophagy, and their interconnections in the context of age-related CVD and endothelial dysfunction. Finally, we discuss pharmacological interventions targeting mitochondrial dysfunction to delay cardiovascular aging and manage CVD. oxidative stress; mitophagy; fusion and fission; neurodegeneration; resveratrol THIS ARTICLE is part of a collection on Mitochondria in Cardiovascular Physiology and Disease. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.Advanced age is associated with excessive incidence and prevalence of cardiovascular disease (CVD). Over 80% of cases of coronary artery disease (CAD) and more than 75% of those of congestive heart failure (CHF) are observed in elderly patients (113). The incidence of CVD, including CAD, CHF, and stroke, increases from 4 -10/1,000 person-years in adults aged 45-54 years to 65-75/1,000 person-years in those older than 85 (112). CVD is also a major cause of chronic disability in advanced age (140). Indeed, subclinical CVD is associated with a decline in physical and cognitive function equivalent to over 5 years of aging (136). Similarly, neurodegenerative disorders, such as vascular dementia and Alzheimer's disease (AD), pose a major problem to global public health (45,90).Although the long-term exposure to cardiovascular risk factors plays a major role in the etiopathogenesis of CVD and neurodegeneration, intrinsic aging of the heart and the vasculature greatly enhances the susceptibility to developing CVD and neurodegenerative conditions in late life (100). The cardiovascular sy...

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Down-regulation of OPA1 alters mouse mitochondrial morphology, PTP function, and cardiac adaptation to pressure overload

Abstract: These results suggest that, in adult cardiomyocytes, OPA1 plays an important role in mitochondrial morphology and PTP functioning. These properties may be critical for cardiac function under conditions of chronic pressure overload.

Cited by 171 publications

References 41 publications

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Tom70 serves as a molecular switch to determine pathological cardiac hypertrophy

Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

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