Role of Bax and Bak in mitochondrial morphogenesis

Bcl-2 family proteins are potent regulators of programmed cell death. Although their intracellular localization to mitochondria and the endoplasmic reticulum has focused research on these organelles, how they function remains unknown. Two members of the Bcl-2 family, Bax and Bak, change intracellular location early in the promotion of apoptosis to concentrate in focal clusters at sites of mitochondrial division. Here we report that in healthy cells Bax or Bak is required for normal fusion of mitochondria into elongated tubules. Bax seems to induce mitochondrial fusion by activating assembly of the large GTPase Mfn2 and changing its submitochondrial distribution and membrane mobility-properties that correlate with different GTP-bound states of Mfn2. Our results show that Bax and Bak regulate mitochondrial dynamics in healthy cells and indicate that Bcl-2 family members may also regulate apoptosis through organelle morphogenesis machineries.     

BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain

Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord. Spinal microglia stimulated by ATP contribute to tactile allodynia, a highly debilitating symptom of pain induced by nerve injury. Signalling between microglia and neurons is therefore an essential link in neuropathic pain transmission, but how this signalling occurs is unknown. Here we show that ATP-stimulated microglia cause a depolarizing shift in the anion reversal potential (E(anion)) in spinal lamina I neurons. This shift inverts the polarity of currents activated by GABA (gamma-amino butyric acid), as has been shown to occur after peripheral nerve injury. Applying brain-derived neurotrophic factor (BDNF) mimics the alteration in E(anion). Blocking signalling between BDNF and the receptor TrkB reverses the allodynia and the E(anion) shift that follows both nerve injury and administration of ATP-stimulated microglia. ATP stimulation evokes the release of BDNF from microglia. Preventing BDNF release from microglia by pretreating them with interfering RNA directed against BDNF before ATP stimulation also inhibits the effects of these cells on the withdrawal threshold and E(anion). Our results show that ATP-stimulated microglia signal to lamina I neurons, causing a collapse of their transmembrane anion gradient, and that BDNF is a crucial signalling molecule between microglia and neurons. Blocking this microglia-neuron signalling pathway may represent a therapeutic strategy for treating neuropathic pain.     

Termination of global warmth at the Palaeocene/Eocene boundary through productivity feedback

The onset of the Palaeocene/Eocene thermal maximum (about 55 Myr ago) was marked by global surface temperatures warming by 5-7 degrees C over approximately 30,000 yr (ref. 1), probably because of enhanced mantle outgassing and the pulsed release of approximately 1,500 gigatonnes of methane carbon from decomposing gas-hydrate reservoirs. The aftermath of this rapid, intense and global warming event may be the best example in the geological record of the response of the Earth to high atmospheric carbon dioxide concentrations and high temperatures. This response has been suggested to include an intensified flux of organic carbon from the ocean surface to the deep ocean and its subsequent burial through biogeochemical feedback mechanisms. Here we present firm evidence for this view from two ocean drilling cores, which record the largest accumulation rates of biogenic barium--indicative of export palaeoproductivity--at times of maximum global temperatures and peak excursion values of delta13C. The unusually rapid return of delta13C to values similar to those before the methane release and the apparent coupling of the accumulation rates of biogenic barium to temperature, suggests that the enhanced deposition of organic matter to the deep sea may have efficiently cooled this greenhouse climate by the rapid removal of excess carbon dioxide from the atmosphere.     

Increased thermohaline stratification as a possible cause for an ocean anoxic event in the Cretaceous period

Ocean anoxic events were periods of high carbon burial that led to drawdown of atmospheric carbon dioxide, lowering of bottom-water oxygen concentrations and, in many cases, significant biological extinction. Most ocean anoxic events are thought to be caused by high productivity and export of carbon from surface waters which is then preserved in organic-rich sediments, known as black shales. But the factors that triggered some of these events remain uncertain. Here we present stable isotope data from a mid-Cretaceous ocean anoxic event that occurred 112 Myr ago, and that point to increased thermohaline stratification as the probable cause. Ocean anoxic event 1b is associated with an increase in surface-water temperatures and runoff that led to decreased bottom-water formation and elevated carbon burial in the restricted basins of the western Tethys and North Atlantic. This event is in many ways similar to that which led to the more recent Plio-Pleistocene Mediterranean sapropels, but the greater geographical extent and longer duration (approximately 46 kyr) of ocean anoxic event 1b suggest that processes leading to such ocean anoxic events in the North Atlantic and western Tethys were able to act over a much larger region, and sequester far more carbon, than any of the Quaternary sapropels.