Mitochondrial HSP90s and tumor cell metabolism.

The control of protein homeostasis, or proteostasis, has been traditionally viewed through the lenses of a general housekeeping function that all cells need, regardless of pathway specification or link to defined cellular responses. A more updated perspective considers proteostasis as an essential adaptive mechanism, taking place in specialized subcellular organelles, and maintaining the functionality of defined cellular networks. Fresh experimental evidence now identifies heat shock protein 90 (HSP90) chaperones as pivotal regulators of proteostasis in mitochondria, selectively in tumor cells. This function connects to a global network of cellular compensation, linking autophagy, endoplasmic reticulum (ER) stress and metabolic reprogramming in a single adaptive continuum, and offers prime opportunities for novel cancer therapeutics.