bims-cytox1 2026-06-21 papers

Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2612098123

SLC25A3 exports mitochondrial copper to metalate cytochrome c oxidase and prevent cuproptosis.

Mohammad Zulkifli, Ifrah Farid, Laura E Oldfather, Vinit C Shanbhag, Scot C Leary, Michael J Petris, Paul A Cobine, Vishal M Gohil.

Copper (Cu) is an essential cofactor for cytochrome c oxidase (CcO), a mitochondrial respiratory chain enzyme that is metalated in the intermembrane space (IMS) primarily using Cu derived from the mitochondrial matrix pool. While Cu import into the matrix depends on the inner membrane carrier SLC25A3, the route by which matrix Cu is exported to the IMS for insertion into CcO has remained a major, unresolved step in intramitochondrial Cu trafficking. Here, we leveraged our recent discovery that the Cu ionophore elesclomol (ES) releases Cu directly into the mitochondrial matrix to show that SLC25A3 is required for exporting Cu to the IMS for CcO metalation. Loss of SLC25A3 decreases mitochondrial Cu content and CcO activity as expected. Strikingly, bypassing the loss of SLC25A3 with ES-mediated Cu delivery to the matrix fails to restore CcO function; rather, it drives toxic Cu retention and triggers cuproptosis, revealing that SLC25A3-facilitated Cu export is the limiting determinant of CcO metalation. Heterologous expression in Lactococcus lactis confirms that SLC25A3 can mediate Cu export. These results suggest that SLC25A3 is the long-sought mitochondrial Cu exporter with a dual role in enabling CcO metalation and gating susceptibility to cuproptosis.

Keywords: SLC25A3; copper; cuproptosis; cytochrome c oxidase; elesclomol

DOI: https://doi.org/10.1073/pnas.2612098123

FEBS Lett. 2026 Jun 16.

Electron transfer between complexes III and IV in S. cerevisiae mitochondrial membranes.

Ana Paula Lobez, Mikael Oliveberg, Peter Brzezinski.

Mitochondrial oxidative phosphorylation relies on cytochrome c transferring electrons between complexes III and IV. Earlier studies using detergent-purified complex III-IV supercomplexes from S. cerevisiae showed that this transfer is limited by two-dimensional cytochrome c diffusion. This study investigates this process in membrane-embedded mitoplasts. The results show that membrane embedment shifts the rate-limiting step from cytochrome c-mediated electron transfer to the catalytic activity of the supercomplex itself. Up to a cytochrome c : supercomplex ratio of unity, turnover increases sharply regardless of ionic strength. At higher ratios, the rate levels out at 15-20 s-1, indicating that the process is no longer limited by salinity-dependent electron transfer, but rather by the catalytic capacity of complex IV.

Keywords: cytochrome bc1; cytochrome c oxidase; electrochemical gradient; electron transfer; energy conversion; membrane protein; proton transfer; respiratory chain; respiratory supercomplex

DOI: https://doi.org/10.1002/1873-3468.70382

Protein Sci. 2026 Jul;35(7): e70682

Co-translational protein targeting to mitochondria in the context of co-translational protein maturation.

Nikita A Kvasov, Yury S Bykov.

Mitochondria import the majority of their proteins from the cytosol, creating a fundamental challenge: precursor proteins must be synthesized, maintained in an import-competent state, and delivered to mitochondrial translocases without premature folding or aggregation. While mitochondrial protein import has been considered a post-translational process, growing evidence shows that a subset of mitochondrial proteins is synthesized in proximity to the organelle. We term this process co-translational targeting, or local translation. It may lead to direct structural coupling of protein synthesis and import, which we term co-translational translocation. New approaches, including selective ribosome profiling, proximity labeling, and RNA imaging, reveal that mitochondrial mRNA localization is highly dynamic and can be driven by both RNA-based and translation-dependent mechanisms. In contrast to the well-defined signal recognition particle pathway at the endoplasmic reticulum, mitochondrial targeting appears to rely on more flexible mechanisms shaped by nascent-chain properties, translation elongation, and coding-sequence features beyond the targeting signal. We discuss how these processes may support mitochondrial biogenesis and proteostasis while also creating vulnerabilities associated with ribosome stalling and precursor quality control. Together, recent findings position mitochondrial protein targeting as an integral part of cellular protein biogenesis and highlight key open questions in the coordination of translation and organelle function.

Keywords: NAC; chaperones; co‐translational import; mRNA localization; mitochondria; protein targeting; translation

DOI: https://doi.org/10.1002/pro.70682

J Clin Invest. 2026 Jun 16. pii: e196687. [Epub ahead of print]

Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.

Most mitochondrial proteins are nuclear encoded, translated in the cytosol, and imported into the mitochondria. Through gene expression analysis and functional assays, we demonstrated that mitochondrial protein import is increased in acute myeloid leukemia (AML) cells compared to normal hematopoietic cells. Increased mitochondrial protein import was positively correlated with increased mitochondrial unfolded protein response (UPRmt), a stress activated pathway of mitochondrial proteases and chaperones that maintains protein solubility and prevents the formation of toxic aggregates. The UPRmt protease LONP1 (Lon Peptidase 1) was upregulated in AML and positively correlated with increased mitochondrial protein import and UPRmt. Genetically or chemically inhibiting the LONP1 ATPase domain induced mitochondrial protein aggregation and selectively killed AML cells with high LONP1 expression while sparing AML cells with low LONP1 expression and normal hematopoietic cells in vitro and in vivo. Thus, we uncovered a critical role of the UPRmt protease LONP1 in buffering stress from mitochondrial protein import in AML.

Keywords: Cancer; Cell biology; Metabolism; Oncology

DOI: https://doi.org/10.1172/JCI196687