IF1: setting the pace of the F1Fo-ATP synthase

Campanella, Michelangelo; Parker, Nadeene; Tan, Choon Hong; Hall, Andrew M.; Duchen, Michael R.

doi:10.1016/j.tibs.2009.03.006

Cited by 127 publications

(119 citation statements)

References 37 publications

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“…S2). An alternative explanation for the constancy of mitochondrial potential may be inhibition of ATP synthase mediated by the H + -sensitive modulator IF1 (40).…”

Section: Resultsmentioning

confidence: 99%

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

Lerchundi

Fernández‐Moncada

Contreras-Baeza

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Neural activity is accompanied by a transient mismatch between local glucose and oxygen metabolism, a phenomenon of physiological and pathophysiological importance termed aerobic glycolysis. Previous studies have proposed glutamate and K + as the neuronal signals that trigger aerobic glycolysis in astrocytes. Here we used a panel of genetically encoded FRET sensors in vitro and in vivo to investigate the participation of NH + 4 , a by-product of catabolism that is also released by active neurons. Astrocytes in mixed cortical cultures responded to physiological levels of NH + 4 with an acute rise in cytosolic lactate followed by lactate release into the extracellular space, as detected by a lactate-sniffer. An acute increase in astrocytic lactate was also observed in acute hippocampal slices exposed to NH + 4 and in the somatosensory cortex of anesthetized mice in response to i.v. NH + 4 . Unexpectedly, NH + 4 had no effect on astrocytic glucose consumption. Parallel measurements showed simultaneous cytosolic pyruvate accumulation and NADH depletion, suggesting the involvement of mitochondria. An inhibitor-stop technique confirmed a strong inhibition of mitochondrial pyruvate uptake that can be explained by mitochondrial matrix acidification. These results show that physiological NH + 4 diverts the flux of pyruvate from mitochondria to lactate production and release. Considering that NH + 4 is produced stoichiometrically with glutamate during excitatory neurotransmission, we propose that NH + 4 behaves as an intercellular signal and that pyruvate shunting contributes to aerobic lactate production by astrocytes.B rain tissue is almost exclusively energized by the oxidation of glucose. However, during neuronal activation, there is a larger increase in local glucose consumption relative to oxygen consumption (1). As this mismatch occurs in the presence of normal or augmented oxygen levels, it has been termed aerobic glycolysis, paralleling the signal detected by functional magnetic resonance imaging (2). Aerobic glycolysis and its associated lactate surge are causally linked to diverse functions of the brain in health and disease (3-10). Two signals are known to trigger aerobic glycolysis in brain tissue: glutamate and K + , which are released by active neurons and stimulate glycolysis in astrocytes (11,12).Neurons produce as much NH + 4 as they produce glutamate, both molecules being stoichiometrically linked in the glutamateglutamine cycle (13). Brain tissue NH + 4 increases within seconds of neural activation (14-16) and is quickly released to the interstitium (17, 18) to be captured by astrocytes through K + channels and transporters (19). It is well established that chronic exposure to pathological levels of NH + 4 such as those observed during liver failure has a major impact on brain metabolism, but it is not known whether this molecule may affect energy metabolism at physiological levels, particularly within the time scale of synaptic transmission. A previous study showed a reversible rise in brain tissue la...

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“…S2). An alternative explanation for the constancy of mitochondrial potential may be inhibition of ATP synthase mediated by the H + -sensitive modulator IF1 (40).…”

Section: Resultsmentioning

confidence: 99%

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

Lerchundi

Fernández‐Moncada

Contreras-Baeza

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…With low glucose, the intra-cristae space was acidified, and no difference was measured between CIV and CV. Reverse ATP synthase has been suggested to maintain Dm H þ by pumping protons out of the matrix when respiratory proton pumping is insufficient 24 . The sink will then become a source.…”

Section: Resultsmentioning

confidence: 99%

Lateral pH gradient between OXPHOS complex IV and F0F1 ATP-synthase in folded mitochondrial membranes

2014

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“…Two specific inhibitors of the mitochondrial ATP synthase, citreoviridin a potent inhibitor produced by fungus, 19 and the endogenous specific inhibitor IF1 20 were applied at the virologic synapse step. Citreoveridin completely inhibited virus transfer at concentrations levels where the toxin had no effect on cell viability or infectivity of the of HIV-1 ( Figure 4A).…”

Section: Specific Inhibitors Of Atp Synthase Activity Block Hiv-1-medmentioning

confidence: 99%

Ectopic ATP synthase facilitates transfer of HIV-1 from antigen-presenting cells to CD4+ target cells

Yavlovich

Viard

Zhou

et al. 2012

Blood

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Antigen-presenting cells (APCs) act as vehicles that transfer HIV to their target CD4+ cells through an intercellular junction, termed the virologic synapse. The molecules that are involved in this process remain largely unidentified. In this study, we used photoaffinity labeling and a proteomic approach to identify new proteins that facilitate HIV-1 transfer. We identified ectopic mitochondrial ATP synthase as a factor that mediates HIV-1 transfer between APCs and CD4+ target cells. Monoclonal antibodies against the β-subunit of ATP synthase inhibited APC-mediated transfer of multiple strains HIV-1 to CD4+ target cells. Likewise, the specific inhibitors of ATPase, citreoviridin and IF1, completely blocked APC-mediated transfer of HIV-1 at the APC-target cell interaction step. Confocal fluorescent microscopy showed localization of extracellular ATP synthase at junctions between APC and CD4+ target cells. We conclude that ectopic ATP synthase could be an accessible molecular target for inhibiting HIV-1 proliferation in vivo.

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IF1: setting the pace of the F1Fo-ATP synthase

Cited by 127 publications

References 37 publications

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

Lateral pH gradient between OXPHOS complex IV and F0F1 ATP-synthase in folded mitochondrial membranes

Ectopic ATP synthase facilitates transfer of HIV-1 from antigen-presenting cells to CD4+ target cells

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