Mitochondrial complex I activity is impaired during HIV-1-induced T-cell apoptosis

Ladha, Jayashree; Tripathy, Manoj K.; Mitra, Debashis

doi:10.1038/sj.cdd.4401668

Cited by 74 publications

(70 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These proteins are the homologues of N. crassa NUO78 (29) and NUO30.4 (60), respectively. Specific downregulation of NDUFA6 (homologue of N. crassa NUO14.8 [41]) but not other complex I subunits induces apoptosis in cells infected with HIV-1 (33). With the possible exception of NDUFA6, the other human complex I subunits were described as proapoptotic.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Rotenone Enhances the Antifungal Properties of Staurosporine

et al. 2010

View full text Add to dashboard Cite

We studied staurosporine-induced cell death in the filamentous fungus Neurospora crassa. The generation of reactive oxygen species during the process appears to be an important signaling event, since addition of the antioxidant glutathione prevents the effects of staurosporine on fungal growth. Selected mutants with mutations in respiratory chain complex I are extremely sensitive to the drug, stressing the involvement of complex I in programmed cell death. Following this finding, we determined that the complex I-specific inhibitor rotenone used in combination with staurosporine results in a synergistic and specific antifungal activity, likely through a concerted action on intracellular glutathione depletion. Paradoxically, the synergistic antifungal activity of rotenone and staurosporine is observed in N. crassa complex I mutants and in Saccharomyces cerevisiae, which lacks complex I. In addition, it is not observed when other complex I inhibitors are used instead of rotenone. These results indicate that the rotenone effect is independent of complex I inhibition. The combination of rotenone and staurosporine is effective against N. crassa as well as against the common pathogens Aspergillus fumigatus and Candida albicans, pointing to its usefulness as an antifungal agent.Programmed cell death (PCD) refers to a genetically controlled process of cellular suicide initiated by endogenous or extrinsic signals. Many of the genes involved are widely conserved from unicellular to multicellular organisms (46). Apoptosis and autophagy, with its particular characteristics, have been recognized as the main categories of PCD (27). The process of PCD is crucial for the development and homeostasis of metazoan organisms and has been implicated in a number of human disorders, including cancer and neurodegenerative and infectious diseases (3,10,25,55).The participation in PCD of mitochondria, the cellular organelles responsible for the production of most cellular ATP in eukaryotes (30), has been well established. Particularly, these organelles have a central role in the intrinsic (mitochondriondependent) pathway of apoptosis, which includes production of reactive oxygen species (ROS), membrane depolarization, ultrastructural changes, and the release of cytochrome c and other proteins (18,50,55). Drugs like staurosporine (STS), an inhibitor of protein kinases, have been used to induce the mitochondrion-dependent pathway of apoptosis (24, 35). Staurosporine (48) and derivatives have been used in clinical trials for cancer therapy (63). The complex I inhibitor rotenone too has been widely used to induce PCD and also extensively applied as a pesticide (11,39,56). Thus, these types of drugs can be employed for the acquisition of fundamental knowledge and for more practical applications, like modulation of the progression of PCD.Modulation of PCD by targeting metabolic pathways involved in the process can be exploited to the benefit of human health in several very significant situations, from cancer therapy (4, 57) to the treatment of f...

show abstract

Section: Discussionmentioning

confidence: 99%

“…2). Complex I has been implicated in cell death induced by human viruses (33,53) or other stimuli in both human and fungal cells (8,31,34,39). Specific subunits of mammalian complex I have also per se been implicated in cell death.…”

Section: Discussionmentioning

confidence: 99%

Rotenone Enhances the Antifungal Properties of Staurosporine

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Other work has shown that complex I inhibition induces apoptosis in mammalian cells (45,46) and that caspase cleavage of the 75-kDa subunit of complex I was claimed to be required for apoptosis (47). Furthermore, it appears that complex I is also involved in virus-induced apoptosis (48,49) and in the interferon-␤ and retinoic acid-induced cancer cell death (50). Our results are in line with these findings and point to a central role of complex I in mediating programmed cell death in filamentous fungi.…”

Section: Discussionmentioning

confidence: 99%

Increased Resistance of Complex I Mutants to Phytosphingosine-induced Programmed Cell Death

Castro

Lemos

Falcão

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

We have studied the effects of phytosphingosine (PHS) on cells of the filamentous fungus Neurospora crassa. Highly reduced viability, impairment of asexual spore germination, DNA condensation and fragmentation, and production of reactive oxygen species were observed in conidia treated with the drug, suggesting that PHS induces an apoptosis-like death in this fungus. Interestingly, we found that complex I mutants are more resistant to PHS treatment than the wild type strain. This effect appears to be specific because it was not observed in mutants defective in other components of the mitochondrial respiratory chain, pointing to a particular involvement of complex I in cell death. The response of the mutant strains to PHS correlated with their response to hydrogen peroxide. The fact that complex I mutants generate fewer reactive oxygen species than the wild type strain when exposed to PHS likely explains the PHS-resistant phenotype. As compared with the wild type strain, we also found that a strain containing a deletion in the gene encoding an AIF (apoptosis-inducing factor)-like protein is more resistant to PHS and H 2 O 2 . In contrast, a strain containing a deletion in a gene encoding an AMID (AIF-homologous mitochondrion-associated inducer of death)-like polypeptide is more sensitive to both drugs. These results indicate that N. crassa has the potential to be a model organism to investigate the molecular basis of programmed cell death in eukaryotic species.

show abstract

“…The perturbations in the metabolite profile were related to increased production of NADH (NADH/NAD + ratio) and FADH 2 due to the dysfunctional RC. Impaired functioning of components of the RC has also been reported as a consequence of HIV infection (Ricci et al 2004;Ladha et al 2005). …”

Section: Metabolic Interpretations Of the Markers Of Hiv Infectionmentioning

confidence: 99%

Qualitative serum organic acid profiles of HIV-infected individuals not on antiretroviral treatment

et al. 2011

View full text Add to dashboard Cite

The first application of gas chromatography mass spectrometry (GC-MS) metabolomics to the analysis of organic acid profiles in sera of asymptomatic HIV-infected individuals (n = 18) compared to uninfected controls (n = 21), is reported here. Several organic acids are well-established diagnostic biomarkers of mitochondrial dysfunction, making the analysis of the organic acid metabolome well suited to monitoring the progressive disruption of mitochondrial structure and function during HIV infection. Using a multifaceted analyticalbioinformatics procedure, at least 10 of these metabolites could be linked to (1) disrupted mitochondrial metabolism, (2) changes in lipid metabolism and (3) oxidative stress, all of which are aberrations caused by HIV infection. Because of the role of the mitochondria in apoptosis, higher levels of this type of cell death in infected (compared to uninfected) individuals was used to support GC-MS data. This study demonstrates that mass spectrometry metabolomics detects biomarkers of mitochondrial dysfunction which could potentially be developed into indicators of HIV infection, perhaps also to monitor disease progression and the response to antiretroviral treatment (ART).

show abstract

Mitochondrial complex I activity is impaired during HIV-1-induced T-cell apoptosis

Cited by 74 publications

References 50 publications

Rotenone Enhances the Antifungal Properties of Staurosporine

Rotenone Enhances the Antifungal Properties of Staurosporine

Increased Resistance of Complex I Mutants to Phytosphingosine-induced Programmed Cell Death

Qualitative serum organic acid profiles of HIV-infected individuals not on antiretroviral treatment

Contact Info

Product

Resources

About