bims-miptne 2026-07-26 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–07–26
seven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Distinct sources and effects of mitochondrial reactive oxygen species.
Peroxisomal ether lipid synthesis regulates cortical neurogenesis and maintains mitochondrial energy homeostasis in radial glial cells.
VAMP7-dependent mitochondria-lysosome contacts contribute to glial mitochondrial dynamics and dopaminergic neuron survival.
HSP90α lactylation orchestrates PGC1α and LRPGC1 nuclear translocation driving mitochondrial biogenesis.
Towards liquid biopsy-based analysis of antitumour immunity.
Direct coupling of human TOM and TIM22 complexes drives mitochondrial carrier import.
Immunostimulatory lipogel implant enhances cancer immunotherapy.

Mol Cell. 2026 Jul 24. pii: S1097-2765(26)00473-9. [Epub ahead of print]

Distinct sources and effects of mitochondrial reactive oxygen species.

Daniel Barnett, Caroline Booraem, Anna G Orr, Adam L Orr.

  Mitochondrial reactive oxygen species (mtROS) have been implicated in aging and disease for decades and are typically viewed as a unitary, non-specific oxidative burden on cells and tissues. However, recent studies have identified at least eleven individual sources of mitochondrial ROS (ISOMRs) and revealed that ISOMRs have distinct, dynamic, and often reversible roles in diverse physiological and pathological processes, including neurodegenerative diseases, immune and metabolic dysregulation, and ischemia-reperfusion injury. This review describes the upstream molecular events that control ISOMR activity, recently developed tools for studying mtROS in general and ISOMRs more specifically, and the evolving perspectives on ISOMR roles in context-specific cell signaling. Future studies to define predictive principles of ISOMR regulation are necessary to open frontiers of redox biology and identify therapeutic strategies for selective modulation of ISOMR-dependent mechanisms in aging and disease.

Keywords:  cell metabolism; cell signaling pathways; complex I; complex III; disease mechanisms; electron leak; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.1016/j.molcel.2026.07.009
Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2600571123

Peroxisomal ether lipid synthesis regulates cortical neurogenesis and maintains mitochondrial energy homeostasis in radial glial cells.

Lin Li, Wenzheng Zou, Yuqing Lv, Yingfei Lu, Jiaqi Liang, Shukui Zhang, Baoyang Hu, Jianwei Jiao.

  Neurogenesis is characterized by dynamic structural changes and functional remodeling of multiple organelles, which interact to form an intricate network that precisely modulates processes including neural progenitor cell self-renewal, neurogenesis, and terminal neuronal development. However, the spatiotemporal dynamics of peroxisomes and their functional contributions within this regulatory network remain incompletely defined during mammalian cortical development. Here, we found that radial glial cells (RGCs) exhibit enriched peroxisome abundance, whereas neural differentiation is associated with reduced peroxisome numbers and increased pexophagy, accompanied by the remodeling of lipid metabolic programs. Acute disruption of peroxisomes by PLAAT3-PEX11 impaired neural differentiation in the embryonic mouse cortex, while PEX7 knockout compromised neurogenic progression in human cortical organoids, supporting a conserved requirement for peroxisomal function during cortical development. Lipidomic and imaging analyses revealed that peroxisome-derived ether lipids were essential for driving neural differentiation and were specifically enriched in mitochondria. Consistently, knockdown of Gnpat, which catalyzes the initial step of ether lipid biosynthesis, reduced neural differentiation, and disrupted mitochondrial structure and function, while batyl alcohol supplementation partially restored these defects. Mechanistically, the ether lipids maintain the structural integrity of mitochondrial cristae and thereby support respiratory chain activity, which in turn promotes oxidative phosphorylation and activates the NAD+ associated signaling. Collectively, this work highlights the precise spatiotemporal regulation of neurogenesis through peroxisomal dynamics and interorganelle crosstalk and identifies ether lipids as a potential therapeutic target for neurodevelopmental disorders.

Keywords:  ether lipids; mitochondria; neurogenesis; peroxisome

DOI:  https://doi.org/10.1073/pnas.2600571123
Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2603069123

VAMP7-dependent mitochondria-lysosome contacts contribute to glial mitochondrial dynamics and dopaminergic neuron survival.

Honglei Wang, Mengxiao Wang, Yu-Ting Tsai, Yi-Hsuan Cheng, Yu-Tung Lin, Chia-Ching Lin, Yi-Hua Lee, Linfang Wang, Shuanglong Yi, Shiping Zhang, Yufeng Pan, Margaret S Ho.

  Although disrupted mitochondrial dynamics in neurons are closely linked to neurodegenerative diseases, far less is known about how mitochondrial dynamics are regulated in glia or whether glial mitochondrial dysfunction contributes to neurodegeneration. Here, we show that the R-SNARE protein VAMP7 regulates the untethering of mitochondria-lysosome contacts (MLCs) in adult fly glia. Glial-specific knockdown of VAMP7 leads to prolonged MLCs and mitochondrial elongation associated with altered fission/fusion dynamics. These VAMP7-deficient mitochondria exhibit hyperpolarized membrane potential, leading to increased reactive oxygen species production, lipid droplet accumulation, and dopaminergic neurodegeneration. Mechanistically, VAMP7 interacts with the GTPase-activating protein TBC1D15-17 to promote Rab7 GTP hydrolysis. Without VAMP7, TBC1D15-17 remains bound to Rab7 but fails to activate its hydrolysis, resulting in elevated GTP-bound Rab7 and impaired MLCs untethering. Consistently, expression of GTP-locked Rab7Q67L or GTPase-activating protein-dead TBC1D15-17ΔGAP phenocopies the mitochondrial defects, while GDP-bound Rab7T22N or wild-type TBC1D15-17 restores the MLC dynamics. Considering that SNARE proteins mediate membrane fusion, our results demonstrate a role for VAMP7 in glial mitochondrial dynamics via organelle contacts, impacting neuron survival in a non-cell-autonomous manner.

Keywords:  VAMP7; glia; mitochondrial dynamics

DOI:  https://doi.org/10.1073/pnas.2603069123
Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2528979123

HSP90α lactylation orchestrates PGC1α and LRPGC1 nuclear translocation driving mitochondrial biogenesis.

Gang Wu, Hongmin Li, Tong He, Min Chen, Xiaoyu Jiang, Mengli Wei, Lei Zhou, Chengyu Li, Jingli Tao, Zhaojun Liu, Ming Shen, Honglin Liu.

  Mitochondrial biogenesis is a fundamental process that ensures energy supply and supports steroidogenesis in ovarian cells. Lactate has recently been identified as a signaling metabolite that promotes mitochondrial biogenesis; however, the underlying regulatory mechanisms remain poorly defined. Here, we identify Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90α) lactylation as a key mediator that links glycolytic metabolism to mitochondrial function. Specifically, lactylation of HSP90α at K58 recruits ULK1, thereby enhancing phosphorylation at S39; lactylation at K616 prevents CDK5-mediated phosphorylation at S596. This dual regulation facilitates the nuclear translocation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and its isoform LRPGC1, which activate NRF1/2-dependent transcription of mitochondrial biogenesis genes, such as Tfb1m, Tfb2m, and Tfam. Functionally, mitochondrial mass expansion both enhances cellular energy metabolism and promotes cholesterol import into mitochondria, thereby driving estrogen biosynthesis. Together, these findings reveal a lactate-HSP90α-PGC1α/LRPGC1 axis that metabolically couples glycolysis to mitochondrial biogenesis and reproductive hormone production, providing insights into the epigenetic regulation of follicular development.

Keywords:  CDK5; HSP90α lactylation; HSP90α phosphorylation; PGC1α/LRPGC1; ULK1

DOI:  https://doi.org/10.1073/pnas.2528979123
Nat Rev Clin Oncol. 2026 Jul 24.

Towards liquid biopsy-based analysis of antitumour immunity.

Klaus Pantel, Doryan Masmoudi, Catherine Alix-Panabières.

Analysis of tissue biopsy samples is the gold-standard approach to cancer diagnosis and patient selection for biomarker-guided therapies. Although spatial analyses of tumour tissue can provide important insights into local antitumour immune responses, repeated tumour biopsy is invasive and rarely feasible for monitoring dynamic immune responses over time. Technical advances have enabled multimodal analyses of cells and cellular products in peripheral blood samples, which can be obtained easily and repeatedly over the course of the disease. These liquid biopsy-based approaches cannot provide spatial information on the tumour immune microenvironment and tumour-derived material can be highly diluted in the circulation, yet they offer a unique opportunity to monitor systemic immune dynamics, anticipate responses to immunotherapies and detect emerging resistance to treatment. Thus, blood-based analyses might complement tumour tissue analysis. In this Review, we discuss insights on systemic antitumour immune responses that can be gained through the analysis of tumour-derived biomarkers in peripheral blood and/or circulating immune cells.

DOI: https://doi.org/10.1038/s41571-026-01181-8
Nat Struct Mol Biol. 2026 Jul 23.

Direct coupling of human TOM and TIM22 complexes drives mitochondrial carrier import.

Xiaolong Liu, Hongjun Cai, Hao Wang, Xueyin Zhou, Yutong Zhang, Shuai Liu, Jiajun Zhu, Long Li.

Metabolite carriers that control essential metabolite transport are imported into mitochondria through the TOM and TIM22 complexes. How TOM and TIM22 coordinate in human mitochondria has remained largely unknown. Here we show that human TOM and TIM22 assemble into a supercomplex that seamlessly couples carrier translocation across the outer and inner membranes, unlike in yeast where the two complexes appear to function separately. Cryo-electron microscopy structures of the human TOM-TIM22 supercomplex reveal unpaired carrier transmembrane segments traversing the TOM channel along a hydrophobic path and exiting through an unexpected lateral groove outside the channel. The membrane-bound small Tim subunits provide the substrate entry site for TIM22, while a membrane-exposed groove of TIM22 serves as the exit for carrier insertion into the inner membrane. These findings provide insights into the human carrier translocation pathway at molecular resolution and establish the TOM-TIM22 supercomplex as a central organizing unit of mitochondrial carrier import.

DOI: https://doi.org/10.1038/s41594-026-01849-w
Nat Nanotechnol. 2026 Jul 23.

Immunostimulatory lipogel implant enhances cancer immunotherapy.

Ying Zhang, Enlai Wang, Shiyang Li, Yufan Yao, Quanlin Shao, Yanfang Wang, Yingjiao He, Mingqi Liu, Xiang Jin, Zhen Gu, Ran Mo.

Cancer stem-like cells contribute to innate tumour immunoresistance and an immunosuppressive tumour microenvironment, leading to poor responses to immune checkpoint inhibitors. Chemotherapeutic agents can elicit tumour immunogenicity by inducing immunogenic cell death to reinforce the therapeutic efficacies of immune checkpoint inhibitors, but suffer from inefficient immunogenic cell death activation in highly resistant cancer stem-like cells. Here we report an immunostimulatory lyotropic liquid-crystal-based lipogel for localized co-delivery of all-trans retinoic acid, a differentiation-inducing drug, and doxorubicin, an immunogenic-cell-death-inducing chemotherapeutic agent with distinct release kinetics. The lipogel is tailored to release the combinatorial drugs in a differential and sustained manner, which fulfils the requirement for enhanced drug synergism in promoting the immunogenic cell death of cancer stem-like cells. Local implantation of the immunostimulatory lipogel elicits an antitumour immune response that is further augmented by an immune checkpoint inhibitor to suppress tumour growth and metastasis, as well as to prevent post-surgical recurrence in murine models of high-stemness tumours.

DOI: https://doi.org/10.1038/s41565-026-02194-1