Mitochondrial proteostasis, regulated by the mitochondrial unfolded protein response (UPR^mt), is crucial for maintenance of cellular functions and survival. Elevated oxidative and proteotoxic stress in mitochondria must be attenuated by the activation of a ubiquitous UPR^mt to promote prostate cancer (PCa) growth. Here we show that the 2 key components of the UPR^mt, heat shock protein 60 (HSP60, a mitochondrial chaperonin) and caseinolytic protease P (ClpP, a mitochondrial protease), were required for the development of advanced PCa. HSP60 regulated ClpP expression via c-Myc and physically interacted with ClpP to restore mitochondrial functions that promote cancer cell survival. HSP60 maintained the ATP-producing functions of mitochondria, which activated the β-catenin pathway and led to the upregulation of c-Myc. We identified a UPR^mt inhibitor that blocked HSP60’s interaction with ClpP and abrogated survival signaling without altering HSP60’s chaperonin function. Disruption of HSP60-ClpP interaction with the UPR^mt inhibitor triggered metabolic stress and impeded PCa-promoting signaling. Treatment with the UPR^mt inhibitor or genetic ablation of Hsp60 inhibited PCa growth and progression. Together, our findings demonstrate that the HSP60-ClpP–mediated UPR^mt is essential for prostate tumorigenesis and the HSP60-ClpP interaction represents a therapeutic vulnerability in PCa.

The first examples of air-stable Co^II paraCEST MRI contrast agents are reported. Amide NH protons on the complexes give rise to CEST peaks that are shifted up to 112 ppm from the bulk water resonance. One complex has multiple CEST peaks that may be useful for ratiometric mapping of pH.

Complexes of Fe(III) that contain a triazacyclononane (TACN) macrocycle, two pendant hydroxyl groups, and a third ancillary pendant show promise as MRI contrast agents. The ancillary group plays an important role in tuning the solution relaxivity of the Fe(III) complex and leads to large changes in MRI contrast enhancement in mice. Two new Fe(III) complexes, one with a third coordinating hydroxypropyl pendant, Fe(L2), and one with an anionic non-coordinating sulfonate group, Fe(L1)(OH₂), are compared. Both complexes have a deprotonated hydroxyl group at neutral pH and electrode potentials representative of a stabilized trivalent iron center. The r₁ relaxivity of the Fe(L1)(OH₂) complex is double that of the saturated complex, Fe(L2), at 4.7 T, 37 °C in buffered solutions. However, variable-temperature ¹⁷O-NMR experiments show that the inner-sphere water of Fe(L1)(OH₂) does not exchange rapidly with bulk water under these conditions. The pendant sulfonate group in Fe(L1)(OH₂) confers high solubility to the complex in comparison to Fe(L2) or previously studied analogues with benzyl groups. Dynamic MRI studies of the two complexes showed major differences in their pharmacokinetics clearance rates compared to an analogue containing a benzyl ancillary group. Rapid blood clearance and poor binding to serum albumin identify Fe(L1)(OH₂) for development as an extracellular fluid contrast agent.