Recent Advances in Targeting Human Mitochondrial AAA+ Proteases to Develop Novel Cancer Therapeutics

The mitochondrion is a vital organelle that performs diverse cellular functions. In this regard, the cell has evolved various mechanisms dedicated to the maintenance of the mitochondrial proteome. Among them, AAA+ ATPase-associated proteases (AAA+ proteases) such as the Lon protease (LonP1), ClpXP complex, and the membrane-bound i-AAA, m-AAA and paraplegin facilitate the clearance of misfolded mitochondrial proteins to prevent the accumulation of cytotoxic protein aggregates. Furthermore, these proteases have additional regulatory functions in multiple biological processes that include amino acid metabolism, mitochondria DNA transcription, metabolite and cofactor biosynthesis, maturation and turnover of specific respiratory and metabolic proteins, and modulation of apoptosis, among others. In cancer cells, the increase in intracellular ROS levels promotes tumorigenic phenotypes and increases the frequency of protein oxidation and misfolding, which is compensated by the increased expression of specific AAA+ proteases as part of the adaptation mechanism. The targeting of AAA+ proteases has led to the discovery and development of novel anti-cancer compounds. Here, we provide an overview of the molecular characteristics and functions of the major mitochondrial AAA+ proteases and summarize recent research efforts in the development of compounds that target these proteases.