CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells

Mitochondrial proteostasis-maintaining mechanisms are crucial for protecting cells from the toxicity of misfolded protein accumulation. Although excessive stress is known to inactivate these mechanisms and thereby induce mitophagy in cancer cells, the detailed molecular mechanisms coordinating these mitochondrial quality control processes remain unclear. Herein, we identify CLPX, a mitochondrial protease subunit, as an iron-sulfur protein, which requires a [4Fe-4S] cluster to bind with CLPP to exert proteolysis function. Iron chelation impairs the assembly of the [4Fe-4S] cluster onto CLPX, thereby disrupting mitochondrial proteostasis maintenance and inducing mitophagy. Furthermore, cysteine deprivation caused by excessive reactive oxygen species accumulation hinders iron-sulfur cluster biosynthesis, thereby undermining CLPX function and inducing mitophagy. Our research elucidates an iron-sulfur cluster-dependent mechanism sustaining mitochondrial proteostasis. Mitochondrial proteostasis mechanisms protect cells from misfolded protein toxicity, but how these quality control processes are coordinated in cancer cells under stress remain unclear. Here, the authors identify mitochondrial protease subunit CLPX as an iron-sulfur protein dependent on a [4Fe-4S] cluster, and elucidate an iron-sulfur cluster-dependent mechanism that sustains mitochondrial proteostasis and regulates mitophagy.