NLRX1 is an essential, druggable regulator of mitochondrial permeability transition

Recent research has identified a crucial regulator of the mitochondrial permeability transition pore (mPTP), a structure that has long been shrouded in mystery. By utilizing two distinct chemotypes of optimized, brain-penetrant mPTP inhibitors as chemical probes, scientists have discovered that the mitochondrial NOD-like receptor NLRX1 serves as a shared target for these inhibitors.

The potency of binding between NLRX1 and the inhibitors correlates with their ability to inhibit the mPTP. Through the use of CRISPR-Cas9-edited human cells and Nlrx1-/- mouse tissues, researchers have proven that NLRX1 is essential for the normal calcium-induced opening of the mPTP. Inhibition of NLRX1 raises the calcium threshold for pore opening, while overexpression of the receptor lowers it, independent of the cyclophilin D protein.

NLRX1 interacts with presumed mPTP components, such as ATP synthase and the adenine nucleotide translocase, in a manner sensitive to the compounds used. This protein also plays a role in maintaining mitochondrial protein homeostasis over extended periods. Notably, the lead compound, GSK900, is orally bioavailable, capable of penetrating the brain, and effective in a neurological injury model where the mPTP plays a key role.

Collectively, these findings, supported by recent genetic studies, firmly establish NLRX1 as an indispensable, CypD-independent regulator of the mPTP. The development of brain-penetrant chemical tools targeting NLRX1 provides valuable insights into the biological processes associated with this essential regulator.