Mitochondrial diseases and genetic defects of ATP synthase

Houštěk, J; Pícková, Andrea; Vojtíšková, Alena; Mráček, Tomáš; Pecina, Petr; Ješina, Pavel

doi:10.1016/j.bbabio.2006.04.006

Cited by 121 publications

(76 citation statements)

References 64 publications

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“…PNPT1 copy numbers decreased more than ten-fold at 9 cm (p<0.001) and by half at 15 cm (p<0.001) after 7 days of treatment ( Figure 5A). To directly assess mitochondrial function, we picked one of the 13 genes encoded by mitochondrial DNA, ATP synthase F0 subunit 6 (ATP6), a key component of the proton channel 34 , and measured its transcription by RT-ddPCR in the 9 cm biopsies of all 15 study participants in the tenofovir arm ( Figure 5B). Because mitochondrial genes are not included on the microarray chips, we had no preexisting information on its expression.…”

Section: Signs Of Mitochondrial Toxicitymentioning

confidence: 99%

Mucosal effects of tenofovir 1% gel

Hladik

Burgener

Ballweber

et al. 2014

Preprint

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BACKGROUND Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against sexual HIV transmission. Because this is a new prevention strategy targeting large numbers of healthy people, we broadly assessed its effects on the mucosa. METHODS AND FINDINGS In MTN-007, a phase 1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% gel, nonoxynol-9 2% gel, placebo gel or no treatment on rectal biopsies taken at baseline, after one application or after seven daily applications (15 subjects/arm). Experiments were repeated using primary vaginal epithelial cells from four healthy women. After seven days of administration, tenofovir 1% gel had broad-ranging biological effects on the rectal mucosa, which were much more pronounced than—but different from—those caused by the detergent nonoxynol-9. Tenofovir profoundly suppressed anti-inflammatory mediators such as interleukin 10; increased T cell densities; caused mitochondrial dysfunction, possibly by blocking PNPT1 expression; and altered regulatory pathways of cell differentiation and survival. Except for leukocyte-derived factors, all these effects were replicated in primary vaginal epithelial cells, which also proliferated significantly faster in tenofovir’s presence. CONCLUSIONS Tenofovir’s suppression of anti-inflammatory activity could diminish its prophylactic efficacy over time. The breadth of mucosal changes, including mitochondrial dysfunction and epithelial proliferation, raises questions about its safety for long-term topical use. These findings suggest that a systems biology evaluation of mucosal effects may be beneficial before advancing to large-scale efficacy trials with topical HIV prevention agents that achieve high, long-lasting local drug concentrations.

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Section: Signs Of Mitochondrial Toxicitymentioning

confidence: 99%

Mucosal effects of tenofovir 1% gel

Hladik

Burgener

Ballweber

et al. 2014

Preprint

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“…Quantitative or qualitative defects in F o F 1 ATP synthase function have been reported to result in the production of ROS (23), and thus, we predicted that gJ might be associated with ROS production, as well. Indeed, gJ was necessary for the induction of ROS in HSV-infected cells, since mutant virus with deletion of Us5 did not induce ROS.…”

Section: Discussionmentioning

confidence: 99%

The Antiapoptotic Herpes Simplex Virus Glycoprotein J Localizes to Multiple Cellular Organelles and Induces Reactive Oxygen Species Formation

Aubert

Chen

Lang

et al. 2008

J Virol

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The Us5 gene of herpes simplex virus (HSV) encodes glycoprotein J (gJ). The only previously reported function of gJ was its ability to inhibit apoptosis. However, the mechanism by which gJ prevents apoptosis is not understood, and it is not known whether gJ mediates additional cellular effects. In this study, we evaluated the expression, localization, and cellular effects of Us5/gJ. Us5 was first expressed 4 h after infection. gJ was detectable at 6 h and was expressed in glycosylated and unglycosylated forms. Us5 was regulated as a late gene, with partial dependency on DNA replication for expression. Us5 expression was delayed in the absence of ICP22; furthermore, expression of Us5 in trans protected cells from apoptosis induced by an HSV mutant with deletion of ICP27, suggesting that the antiapoptotic effects of ICP22 and ICP27 are mediated in part through effects on gJ expression. Within HSVinfected or Us5-transfected cells, gJ was distributed widely, especially to the endoplasmic reticulum, trans-Golgi network, and early endosomes. gJ interacted with F o F 1 ATP synthase subunit 6 by a yeast two-hybrid screen and had strong antiapoptotic effects, which were mediated by protein rather than mRNA. Antiapoptotic activity required the extracellular and transmembrane domains of gJ, but not the intracellular domain. Consistent with inhibition of F o F 1 ATP synthase function, Us5 was required for HSV-induced reactive oxygen species (ROS) formation, and gJ was sufficient to induce ROS in Us5-transfected cells. Thus, HSV gJ is a multifunctional protein, modulating other cellular processes in addition to inhibition of apoptosis.

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“…Examples of quantitative defects are those in which the cellular content of the enzyme is reduced to less than 30%. Apparently, these disorders are caused by different nuclear genetic defects that remain to be identified, but most of them display a uniform fatal phenotype with onset in newborns characterized by lactic acidosis and hypertrophic cardiomyopathy (Houstek et al, 2006). In both types of ATP synthase disorders, hyperpolarization due to decreased ATP synthesis promotes ROS production by the respiratory chain, an event that can contribute to the clinical phenotypes as suggested by the beneficial effect of antioxidants observed in NARP cells (Mattiazzi et al,.…”

Section: Disorders Related To Atp Synthasementioning

confidence: 99%

“…2006). The impaired ATP synthesis mainly affects brain tissue and at high mutation load, up to approximately 95%, the heteroplasmic ATP6 gene mutations manifest as neuropathy, ataxia, retinitis pigmentosa (NARP) or as fatal encephalopathy known as Leigh syndrome (Houstek et al, 2006). Examples of quantitative defects are those in which the cellular content of the enzyme is reduced to less than 30%.…”

Section: Disorders Related To Atp Synthasementioning

confidence: 99%

“…MS and protein sequencing have shown that the stored protein is structurally identical to the normal mitochondrial subunit c ). Up-and down-regulation of ATP synthase biogenesis has been observed under different pathophysiological conditions (Houstek et al, 2006). We developed polyspecific antibodies directed against the whole human mitochondrial subproteome by hyperimmunization of rabbits with purified skeletal muscle mitochondria, which allowed detection of upregulation of ATP synthase, in muscle biopsies from patients affected by MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) which are characterized by a drastic reduction of OXPHOS complex 1 (Loro et al,.…”

Section: Disorders Related To Atp Synthasementioning

confidence: 99%

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