bims-mitpro 2026-08-23 papers

Issue of 2026–08–23
three papers selected by
Andreas Kohler, Umeå University

Cell Chem Biol. 2026 Aug 20. pii: S2451-9456(26)00283-7. [Epub ahead of print]33(8): 1071-1073

Allosteric rewiring of mitochondrial stress signaling through Miro1.

In this issue of Cell Chemical Biology, Chandra and colleagues1 demonstrate that allosteric modulation of the mitochondrial protein Miro1 can selectively reprogram mitochondrial stress signaling. Chemical targeting of a single molecular hub can produce distinct responses in disease-relevant cell types, despite acting within a broadly conserved stress pathway.

DOI: https://doi.org/10.1016/j.chembiol.2026.07.011

Chem Biol Interact. 2026 Aug 21. pii: S0009-2797(26)00418-7. [Epub ahead of print] 112310

PGAM5-mediated VDAC1 oligomerization Facilitates Ponatinib-Induced Cardiotoxicity via Disrupting the Mitophagy-Mitochondrial unfolded protein response Synergistic Defense Crosstalk.

Yuyu Li, Dandan Yuan, Haitao Zhou, Mengxia Zhang, Maoxiang Zhao, Haowen Zhuang, Jing Cui, Junyan Wang, Yukun Li.

OBJECTIVES: Ponatinib is an effective tyrosine kinase inhibitor for chronic myeloid leukemia with the T315I mutation, but its clinical use is often limited by serious cardiovascular toxicity. Although mitochondrial dysfunction has been implicated in this process, the upstream stress-sensing mechanism that converts ponatinib exposure into collapse of mitochondrial quality control (MQC) remains poorly defined. We therefore investigated whether the PGAM5/VDAC1 axis mediates ponatinib-induced cardiac injury by coordinately disrupting mitophagy and the mitochondrial unfolded protein response (UPRmt).
METHODS: Cardiomyocyte-specific PGAM5 knockout mice (Pgam5_cko) and littermate controls (Pgam5_f/f) were fed a high-fat diet and then exposed to ponatinib. Cardiac function and adult cardiomyocyte contractility were assessed by echocardiography and IonOptix analysis. Single-cell RNA sequencing, in vivo genetic loss-of-function models, and HL-1 cells with stable Pgam5 knockdown were used to define the underlying mechanism. MQC status, including mitophagy and UPRmt, was evaluated by fluorescence imaging, RT-qPCR, western blotting, and biochemical assays.
RESULTS: Ponatinib markedly increased PGAM5 expression in the heart and induced contractile dysfunction, inflammatory activation, and cardiomyocyte apoptosis. These changes were substantially attenuated in Pgam5_cko mice. Mechanistically, ponatinib promoted pathological oligomerization of the outer mitochondrial membrane protein VDAC1 in a PGAM5-dependent manner. This event was accompanied by simultaneous suppression of PINK1/Parkin-related mitophagy and the UPRmt program, resulting in mitochondrial fragmentation, oxidative stress, and impaired bioenergetic function. At the functional level, loss of PGAM5 restored MQC and preserved cardiac performance under ponatinib stress. Importantly, forced VDAC1 oligomerization with arsenic trioxide largely abolished the protective effects of PGAM5 deficiency, supporting VDAC1 oligomerization as a critical downstream event in this pathway.
CONCLUSION: These findings identify the PGAM5/VDAC1 axis as a key mechanism linking ponatinib stress to coordinated failure of MQC in the heart. By simultaneously disabling mitophagy and UPRmt, this pathway drives mitochondrial dysfunction and cardiac injury. Targeting PGAM5-dependent VDAC1 oligomerization may therefore represent a potential strategy for limiting ponatinib-associated cardiotoxicity.

Keywords: Mitochondrial unfolded protein response; Mitophagy; PGAM5/VDAC1 axis; Ponatinib; cardiotoxicity

DOI: https://doi.org/10.1016/j.cbi.2026.112310

bioRxiv. 2026 Aug 01. pii: 2026.07.31.742112. [Epub ahead of print]

Combinatorial sequence elements fine-tune mitochondrial protein import to facilitate dual localization.

Youmian Yan, Lianjie Wei, Thomas Schodl, Keri-Lyn Kozul, Maria Behrens, Stephen P Plassmeyer, Alex S Holehouse, Natalie M Niemi.

The dual targeting of mitochondrial proteins regulates a host of cellular processes, including metabolism, cofactor biosynthesis, mitophagy, and stress responsiveness. Despite this importance, the mechanisms by which proteins dually localize are incompletely defined. Here, we identify multiple sequence elements that compromise the matrix localization of the phosphatase PPTC7 to facilitate its accumulation at the outer mitochondrial membrane (OMM), where it regulates mitophagy. We find that PPTC7 has a moderately 'weak' presequence, but this feature is insufficient to promote dual targeting of a generic cargo protein. Instead, our data suggest that a recently evolved glycine stretch decreases the helical potential of the PPTC7 presequence, weakening its import efficiency in vitro and in cells. Deletion of these glycine residues improves PPTC7 in vitro import and enrichment within the mitochondrial matrix, but only partially suppresses PPTC7-mediated regulation of mitophagy at the OMM. These data suggested additional elements may contribute to PPTC7 dual localization, including its mature phosphatase domain which has robust thermal stability and becomes further stabilized to an import-incompetent state upon binding to its requisite enzymatic co-factor manganese. Simultaneous increases in presequence strength and denaturation of the PPTC7 phosphatase domain are required to promote import in vitro, underscoring the multifactorial challenges associated with its matrix targeting. These data suggest that sequence-specific features can work combinatorially to impart dual-localization capacity to mitochondrial proteins, enabling functions across cellular compartments.

DOI: https://doi.org/10.64898/2026.07.31.742112