Under certain circumstances, a normally innocuous key molecular intermediate of regular cell metabolism, farnesyl pyrophosphate (FPP), can trigger neuronal lysis and cell death, according to a study led by Chinese researchers at Tsinghua and Peking universities in Beijing.
Reported in the April 26, 2021, edition of the open-access journal PLOS Biology, the discovery should not only improve our understanding of ischemic stroke damage, but also offer a potentially important new drug target via which to reduce that ischemic damage.
Homeostasis between cell survival and death is dynamically regulated throughout life, with cell death occurring under both physiological conditions, such as aging, and pathological states including ischemia and disease.
Moreover, "bioactive mediators released after cell death can endanger the local microenvironment by recruiting inflammatory cells and triggering secondary cell death," said study leader Wanli Liu, a professor in the Institute of Immunology at Tsinghua University.
Among these microenvironmental factors, FPP is an important intermediate in the mevalonate (MVA) pathway, which contributes to cellular processes including protein synthesis, energy production, and cell membrane construction.
While investigating immune cell functional regulators, Liu and his close collaborators, Yonghui Zhang, an associate professor in the School of Pharmaceutical Sciences at Tsinghua University, and Yong Zhang, a professor in the Neuroscience Research Institute at Peking University, discovered that, at high extracellular concentrations, FPP caused rapid and extensive cell death.
"We found that FPP, containing a lipophilic hydrocarbon chain and lipophobic pyrophosphate head, is a danger signal that induces acute cell death in a dose-dependent manner, with this cytotoxic effect depending on FPP structure, especially the length of the unsaturated hydrocarbon tail," said Liu.
Depletion of extracellular calcium was then demonstrated to prevent the lethal effect of FPP, "suggesting that FPP-induced cytotoxicity relies on extracellular calcium influx to the cytosol," noted Liu.
Importantly, the knockout of frequently used calcium channels showed that one such channel, transient receptor potential melastatin 2 (TRPM2), contributed to FPP-induced cell death, "whereas inhibiting TRPM2 activity could significantly inhibited alleviate cell death effects," Liu told BioWorld Science.
In addition, electrophysiological recordings showed that FPP evoked TRPM2 channel opening.
Under normal physiological conditions, FPP is present in the microenvironment at concentrations that are much too low to trigger cell death.
However, that changes with ischemic stroke, "as the MVA pathway becomes highly active in neurons, with stress-induced necrosis leading to the rapid release of cellular contents, which significantly elevate the levels of otherwise-rare microenvironmental biomolecules such as FPP," noted Liu.
He and his team then demonstrated a large increase in the FPP concentration in a mouse model of ischemic injury, namely a middle cerebral artery occlusion (MCAO) model, while preadministration of a calcium channel blocker significantly reduced the extent of that injury.
Moreover, "the application of inhibitors that prevent the metabolic production of FPP also reduced the extent of the MCAO injury in the mouse model," Liu said.
Taken together, these results suggest that FPP could represent a new approach to reducing stroke damage, either by inhibiting TRPM2 to reduce the calcium influx or by targeting its metabolic synthesizing pathway.
However, "much remains to be learned about this new cell death pathway, in particular the time-window during which such interventions might be optimally effective as therapy," said Liu.
"These findings nevertheless point to novel, potentially druggable targets via which to treat post-stroke ischemic injury," he said.
"However, given the highly complex nature of human ischemic injury, the targeting of FPP function in combination with currently available therapies may be necessary to achieve optimal therapeutic outcomes."