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Mitochondria-Targeting Metal Complexes: Design Principles, Mechanisms of Action, and Translational Perspectives
Donatella Coradduzza1, Giacomo Senzacqua2, Rosita Cappai2
1Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy.
Biomolecules
|July 28, 2026
Summary
Mitochondria-targeting metal complexes (MTMCs) offer a distinct approach to cancer therapy by exploiting mitochondrial vulnerabilities. Rigorous analytical and pharmacokinetic studies are crucial for advancing MTMC clinical translation.
Area of Science:
- Metallopharmaceuticals
- Mitochondrial Biology
- Cancer Therapeutics
Background:
- Mitochondria-targeting metal complexes (MTMCs) represent a novel class of metallopharmaceuticals distinct from traditional platinum drugs.
- MTMCs leverage unique mitochondrial features like membrane potential, reactive oxygen species (ROS), and limited DNA repair capacity.
Purpose of the Study:
- To systematically review and analyze the latest trends in MTMC drug design, mechanisms of action, and analytical techniques.
- To critically evaluate translational barriers and clinical failures in MTMC development.
- To establish a clear hierarchy for evidence of mitochondrial localization.
Main Methods:
- Systematic literature search of PubMed, Web of Science, Scopus, and Google Scholar (2016-2026).
- Inclusion criteria focused on subcellular localization evidence and bioenergetic endpoints.
- Analysis of studies involving various metal complexes (Pt, Ru, Au, Ir, Os, Re, V) and metal-organic frameworks.
Main Results:
- 147 studies identified, detailing mechanisms targeting electron transport chain complexes, ROS production, mitochondrial membrane permeabilization, and mitochondrial DNA (mtDNA) damage.
- Recurrent finding of multi-modal cell death (apoptosis, ferroptosis, necroptosis, autophagy).
- Highlighted limitations of relying solely on membrane potential for targeting and the need for speciation-aware pharmacokinetics.
Conclusions:
- Translational success of MTMCs hinges on analytical rigor, speciation-aware pharmacokinetics, organelle-level safety monitoring, and biomarker-guided patient selection.
- Distinguishing true MTMCs from merely mitochondria-localizing agents requires robust evidence.
- Future progress depends on analytical advancements rather than solely new chemotypes.
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