CHCHD1 Activators

CHCHD1 activators comprise a heterogeneous collection of compounds that influence CHCHD1 function through various mechanisms, predominantly related to the modulation of oxidative stress responses, endoplasmic reticulum (ER) stress responses, and metabolic stress responses. Several of these compounds, such as Cobalt(II) chloride and Sodium arsenite, operate through the activation of stress response pathways, leading to the transcriptional upregulation of CHCHD1, which in turn enhances its functional activity. Cobalt(II) chloride induces a hypoxic response through HIF-1α stabilization, upregulating the transcription of CHCHD1. Sodium arsenite, on the other hand, induces oxidative stress that leads to the activation of the NRF2 pathway, which subsequently upregulates CHCHD1.

Other CHCHD1 activators work by inducing ER stress or metabolic stress. Tunicamycin, Thapsigargin, Verapamil, Salubrinal, and TUDCA all induce ER stress, triggering the unfolded protein response (UPR) pathway in which CHCHD1 is involved, leading to enhanced CHCHD1 activity. The induction of metabolic stress, through compounds such as 2-Deoxy-D-glucose, Rapamycin, Metformin, AICAR, and Phenformin, enhances the transcription of CHCHD1 by activating AMPK. These compounds inhibit glycolysis or mTOR, or directly activate AMPK, enhancing CHCHD1 activity. Importantly, all these compounds induce specific stress responses or changes in cellular metabolic status that necessitate the increased activity of CHCHD1, rather than simply upregulating its expression.