{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:40:12Z","timestamp":1792723212671,"version":"4.5.0"},"reference-count":177,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:00:00Z","timestamp":1783123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Mitochondria-targeting metal complexes (MTMCs) are a mechanistically distinct class of metallopharmaceuticals. Unlike first-generation platinum drugs that form nuclear DNA adducts, MTMCs exploit organelle-specific vulnerabilities such as hyperpolarised mitochondrial membrane potential (\u0394\u03a8m), elevated reactive oxygen species (ROS), limited mitochondrial DNA (mtDNA) repair capacity, and redox-dependent enzymes such as thioredoxin reductase (TrxR). We systematically searched PubMed, Web of Science, Scopus, and Google Scholar databases for studies published between 2016 and 2026, applying predefined inclusion criteria that included subcellular localization evidence and functional bioenergetic endpoints. The search identified 147 studies covering Pt(II\/IV), Ru(II\/III), Au(I\/III), Ir(III), Os(II), Re(I), and V(IV\/V) complexes and metal\u2013organic framework nanoplatforms. Mechanistic evidence converges on four intramitochondrial target categories: inhibition of ETC (Electron Transport Chain) Complexes I\/III with consequent ATP depletion; ROS overproduction, coupled with glutathione and TrxR depletion; outer mitochondrial membrane permeabilization and intrinsic apoptotic cascade activation; and mtDNA damage within a compartment limited to base excision repair. Multi-modal cell death\u2014the co-occurrence of apoptosis, ferroptosis, necroptosis, and autophagic cell death\u2014was a recurrent finding across the reviewed studies. This review thoroughly surveys the latest trends in MTMC drug design (metals, ligand structures, and mechanisms of action) and summarises analytical techniques for speciation, pharmacokinetics, safe monitoring, and resistance, while critically analysing translational barriers and clinical failures. To address the field\u2019s inconsistent terminology, we introduce an explicit localization evidence hierarchy that distinguishes mitochondria-targeting complexes (through quantitative ICP-MS fractionation or co-localization with defined Pearson\/Manders coefficients) from simply mitochondria-localising or mitochondria-perturbing agents, and we apply it throughout. We also point out that the idea of selectivity being purely driven by membrane voltage (\u0394\u03a8m) and thermodynamics is constrained by membrane and protein binding, as well as the transmembrane pH gradient, kinetic limitations, and demonstrated heterogeneity of cancer-cell membrane potential, and, as such, the functional mitochondrial effects must not be equated with mitochondrial accumulation. Since elemental quantification cannot distinguish intact complex from protein adducts and decomposition products, speciation-aware pharmacokinetics emerges as a prerequisite for a credible exposure\u2013response interpretation. The translational progress will depend less on new chemotypes than on this analytical and pharmacokinetic rigour, together with organelle-level safety monitoring and biomarker-guided patient selection.<\/jats:p>","DOI":"10.3390\/biom16070987","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T14:56:42Z","timestamp":1783349802000},"page":"987","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mitochondria-Targeting Metal Complexes: Design Principles, Mechanisms of Action, and Translational Perspectives"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8978-0490","authenticated-orcid":false,"given":"Donatella","family":"Coradduzza","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0251-7315","authenticated-orcid":false,"given":"Giacomo","family":"Senzacqua","sequence":"additional","affiliation":[{"name":"Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6544-8311","authenticated-orcid":false,"given":"Rosita","family":"Cappai","sequence":"additional","affiliation":[{"name":"Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4304-0251","authenticated-orcid":false,"given":"Serenella","family":"Medici","sequence":"additional","affiliation":[{"name":"Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1042\/bio_2022_119","article-title":"Beyond ATP, new roles of mitochondria","volume":"44","author":"Chakrabarty","year":"2022","journal-title":"Biochemist"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tao, J., Yuan, Z., and Zhou, M. 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