The preservation of mitochondrial function and integrity is critical for cell viability. Under stress conditions,
unfolded, misfolded or damaged proteins accumulate in a certain compartment of the organelle, interfering
with oxidative phosphorylation and normal mitochondrial functions. In stress conditions, several mechanisms, including
mitochondrial unfolded protease response (UPRmt), fusion and fission, and mitophagy are engaged to restore
normal proteostasis of the organelle.
Mitochondrial proteases are a family of more than 20 enzymes that not only are involved in the UPRmt, but actively
participate at multiple levels in the stress-response system. Alterations in their expression levels, or mutations that determine loss
or gain of function of these proteases deeply impair mitochondrial functionality and can be associated with the onset of inherited diseases,
with the development of neurodegenerative disorders and with the process of carcinogenesis. In this review, we focus our attention
on six of them, namely CLPP, HTRA2 and LONP1, by analysing the current knowledge about their functions, their involvement in the
pathogenesis of human diseases, and the compounds currently available for inhibiting their functions.