bims-miptne 2025-05-04 papers

Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00398-5. [Epub ahead of print]44(5): 115627

Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.

Jillian S Weissenrieder, Jessica Peura, Usha Paudel, Nikita Bhalerao, Natalie Weinmann, Calvin Johnson, Maximilian Wengyn, Rebecca Drager, Emma Elizabeth Furth, Karl Simin, Marcus Ruscetti, Ben Z Stanger, Anil K Rustgi, Jason R Pitarresi, J Kevin Foskett.

Endoplasmic reticulum to mitochondria Ca2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in patients with PDAC. In isogenic murine PDAC models, Mcu deletion (McuKO) ablated mitochondrial Ca2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to-mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca2+ uptake reduced the expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGF-β. Snail re-expression and TGF-β treatment rescued deficits in McuKO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.

Keywords: CP: Cancer; CP: Metabolism; EMT; MCU; PDAC; calcium signaling; cancer; epithelial-to-mesenchymal transition; metabolism; mitochondria; pancreas; uniporter

DOI: https://doi.org/10.1016/j.celrep.2025.115627

Cell Signal. 2025 Apr 26. pii: S0898-6568(25)00250-5. [Epub ahead of print]132 111837

Diminution of HSP75 disrupts intestinal epithelial barrier by inciting mPTP opening in ulcerative colitis.

Hao Liang, Xinyu Bai, Rui Zhu, Huixian Song, Yinglei Miao, Yunling Wen, Junkun Niu, Fengrui Zhang.

Ulcerative colitis is an idiopathic, chronic inflammatory disorder. The disruption of intestinal epithelial barrier caused by excessive apoptosis of intestinal epithelial cells is a pivotal factor in the etiology and pathology. The mitochondrial pathway is the most significant apoptosis mode of intestinal epithelial cells, which was regulated by the mitochondrial permeability transition pore(mPTP). However, the precise mechanism remains elusive. As a crucial molecule in combating stress and maintaining mitochondrial homeostasis, the heat shock protein 75(HSP75) may play a vital role in regulating the openness of the mPTP. In our research, we ascertained that HSP75 was significantly diminished in the intestinal mucosal of UC patients and experimental colitis mice, concomitantly with the disruption of intestinal epithelial barrier. Furthermore, a negative correlation between HSP75 and the openness of mPTP, mitochondrial-driven apoptosis, and disruption of intestinal epithelial barrier has been demonstrated in vivo and vitro. Secondly, HSP75 level is negatively correlated with the expression of ANT, VDAC, and PiC, which considered to be the components of mPTP. However, the CypD is unaffected by HSP75. Finally, HSP75 altered the synthesis of ANT, VDAC, PiC and the acetylation modification of ANT, but there is no direct interaction between HSP75 and mPTP component proteins. In conclusion, the present study demonstrated that HSP75 significantly decreased in the intestinal mucosa of UC, and preliminarily revealed a novel mechanism of HSP75 regulating the synthesis and openness of mPTP in the intestinal epithelial cells(IECs) of UC, suggesting that the targeted intestinal mucosa supplementation of HSP75 is anticipated to reverse the pathological process.

Keywords: Heat shock protein 75; Intestinal epithelial barrier; Mitochondrial permeability transition pore; Mitochondrial-driven apoptosis; Ulcerative colitis

DOI: https://doi.org/10.1016/j.cellsig.2025.111837

Aging Cell. 2025 Apr 25. e70054

3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes.

Estevão Scudese, Andrea G Marshall, Zer Vue, Vernat Exil, Benjamin I Rodriguez, Mert Demirci, Larry Vang, Edgar Garza López, Kit Neikirk, Bryanna Shao, Han Le, Dominique Stephens, Duane D Hall, Rahmati Rostami, Taylor Rodman, Kinuthia Kabugi, Jian-Qiang Shao, Margaret Mungai, Salma T AshShareef, Innes Hicsasmaz, Sasha Manus, Celestine N Wanjalla, Aaron Whiteside, Revathi Dasari, Clintoria R Williams, Steven M Damo, Jennifer A Gaddy, Brian Glancy, Estélio Henrique Martin Dantas, André Kinder, Ashlesha Kadam, Dhanendra Tomar, Fabiana Scartoni, Matheus Baffi, Melanie R McReynolds, Mark A Phillips, Anthonya Cooper, Sandra A Murray, Anita M Quintana, Nelson Wandira, Okwute M Ochayi, Magdalene Ameka, Annet Kirabo, Sepiso K Masenga, Chanel Harris, Ashton Oliver, Pamela Martin, Amadou Gaye, Olga Korolkova, Vineeta Sharma, Bret C Mobley, Prasanna Katti, Antentor Hinton.

Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.

Keywords: 3D reconstruction; MFN‐2; aging; exercise; human skeletal muscle; mitochondria

DOI: https://doi.org/10.1111/acel.70054

ACS Biomater Sci Eng. 2025 Apr 25.

Platelet Extracellular Vesicles as Natural Delivery Vehicles for Mitochondrial Dysfunction Therapy?

Hsien Chang Yeh, Kirti Gupta, Ya-Hsuan Lu, Abinaya Srinivasan, Liling Delila, Nguyen Tran Hai Yen, Ariunjargal Nyam-Erdene, Thierry Burnouf.

Mitochondria are vital for energy production, metabolic regulation, and cellular signaling. Their dysfunction is strongly implicated in neurological, cardiovascular, and muscular degenerative diseases, where energy deficits and oxidative stress accelerate disease progression. Platelet extracellular vesicles (PEVs), once called "platelet dust", have emerged as promising agents for mitigating mitochondrial dysfunction. Like other extracellular vesicles (EVs), PEVs carry diverse molecular cargo and surface markers implicated in disease processes and therapeutic efficacy. Notably, they may possibly contain intact or partially functional mitochondrial components, making them tentatively attractive for targeting mitochondrial damage. Although direct research on PEVs-mediated mitochondrial rescue remains limited, current evidence suggests that PEVs can modulate diseases associated with mitochondrial dysfunction and potentially enhance mitochondrial health. This review explores the therapeutic potential of PEVs in neurodegenerative and cardiovascular disorders, highlighting their role in restoring mitochondrial health. By examining recent advancements in PEVs research, we aim to shed light on novel strategies for utilizing PEVs as therapeutic agents. Our goal is to underscore the importance of further fundamental and applied research into PEVs-based interventions, as innovative tools for combating a wide range of diseases linked to mitochondrial dysfunction.

Keywords: exosomes; extracellular vesicles; microvesicles; oxidative stress; platelet

DOI: https://doi.org/10.1021/acsbiomaterials.5c00473

EMBO Rep. 2025 Apr 29.

Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.

Marcos Zamora-Dorta, Sara Laine-Menéndez, David Abia, Pilar González-García, Luis C López, Paula Fernández-Montes, Enrique Calvo, Jesús Vázquez, José Antonio Enríquez, Eduardo Balsa.

Defects in mitochondrial oxidative metabolism underlie many genetic disorders with limited treatment options. The incomplete annotation of mitochondrial proteins highlights the need for a comprehensive gene inventory, particularly for Oxidative Phosphorylation (OXPHOS). To address this, we developed a CRISPR/Cas9 loss-of-function library targeting nuclear-encoded mitochondrial genes and conducted galactose-based screenings to identify novel regulators of mitochondrial function. Our study generates a gene catalog essential for mitochondrial metabolism and maps a dynamic network of mitochondrial pathways, focusing on OXPHOS complexes. Computational analysis identifies RTN4IP1 and ECHS1 as key OXPHOS genes linked to mitochondrial diseases in humans. RTN4IP1 is found to be crucial for mitochondrial respiration, with complexome profiling revealing its role as an assembly factor required for the complete assembly of complex I. Furthermore, we discovered that ECHS1 controls oxidative metabolism independently of its canonical function in fatty acid oxidation. Its deletion impairs branched-chain amino acids (BCAA) catabolism, disrupting lipoic acid-dependent enzymes such as pyruvate dehydrogenase (PDH). This deleterious phenotype can be rescued by restricting valine intake or catabolism in ECHS1-deficient cells.

Keywords: CRISPR Screening; ECHS1; Mitochondria; OXPHOS; RTN4IP1

DOI: https://doi.org/10.1038/s44319-025-00459-9

J Biol Chem. 2025 Apr 23. pii: S0021-9258(25)00368-0. [Epub ahead of print] 108519

CRAC channel activity pulsates during cytosolic Ca2+ oscillations.

Yu-Ping Lin, Erica Scappini, Gary Mirams, Charles J Tucker, Anant B Parekh.

Intracellular Ca2+ ions are used as second messengers throughout the phylogenetic tree. They are indispensable for diverse biological processes ranging from fertilization to cell death. In Metazoans, signaling information is conveyed via the amplitude, frequency and spatial profile of cytosolic Ca2+ oscillations. In non-excitable cells, these oscillations generally arise from regenerative release of Ca2+ from inositol 1,4,5-trisphosphate (InsP3)-sensitive intracellular stores, which are refilled by entry of Ca2+ through Ca2+ release-activated Ca2+ (CRAC) channels in the plasma membrane. However, the precise contribution of these store-operated CRAC channels to Ca2+ oscillations has remained controversial for decades. One view proposes that CRAC channels remain open throughout stimulation, functioning as the pacemaker in setting Ca2+ oscillation frequency. An alternative hypothesis is that channel activity oscillates in parallel with InsP3-driven regenerative Ca2+ release. Here, by tethering a genetically encoded Ca2+ indicator to the pore- forming subunit of the CRAC channel, Orai1, we distinguish between these hypotheses and demonstrate that CRAC channel activity fluctuates in phase with cytosolic Ca2+ oscillations during physiological levels of stimulation. We also find that spatially distinct CRAC channel clusters fire in a coordinated manner, revealing that CRAC channels are not independent units but might function in a synchronized manner to provide pulses of Ca2+ signal at the same time.

Keywords: Ca(2+) oscillations; Ca(2+) signaling; Orai1; ion channels; receptors

DOI: https://doi.org/10.1016/j.jbc.2025.108519