bims-miptne 2025-02-16 papers

Acta Neuropathol Commun. 2025 Feb 13. 13(1): 28

Disruption of mitochondrial homeostasis and permeability transition pore opening in OPA1 iPSC-derived retinal ganglion cells.

Michael Whitehead, Joshua P Harvey, Paul E Sladen, Giada Becchi, Kritarth Singh, Yujiao Jennifer Sun, Thomas Burgoyne, Michael R Duchen, Patrick Yu-Wai-Man, Michael E Cheetham.

Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, characterised by the selective loss of retinal ganglion cells (RGCs). Over 60% of DOA cases are caused by pathogenic variants in the OPA1 gene, which encodes a dynamin-related GTPase protein. OPA1 plays a key role in the maintenance of the mitochondrial network, mitochondrial DNA integrity and bioenergetic function. However, our current understanding of how OPA1 dysfunction contributes to vision loss in DOA patients has been limited by access to patient-derived RGCs. Here, we used induced pluripotent stem cell (iPSC)-RGCs to study how OPA1 dysfunction affects cellular homeostasis in human RGCs. iPSCs derived from a DOA+ patient with the OPA1 R445H variant and isogenic CRISPR-Cas9-corrected iPSCs were differentiated to iPSC-RGCs. Defects in mitochondrial networks and increased levels of reactive oxygen species were observed in iPSC-RGCs carrying OPA1 R445H. Ultrastructural analyses also revealed changes in mitochondrial shape and cristae structure, with decreased endoplasmic reticulum (ER): mitochondrial contact length in DOA iPSC-RGCs. Mitochondrial membrane potential was reduced and its maintenance was also impaired following inhibition of the F1Fo-ATP synthase with oligomycin, suggesting that mitochondrial membrane potential is maintained in DOA iPSC-RGCs through reversal of the ATP synthase and ATP hydrolysis. These impairments in mitochondrial structure and function were associated with defects in cytosolic calcium buffering following ER calcium release and store-operated calcium entry, and following stimulation with the excitatory neurotransmitter glutamate. In response to mitochondrial calcium overload, DOA iPSC-RGCs exhibited increased sensitivity to opening of the mitochondrial permeability transition pore. These data reveal novel aspects of DOA pathogenesis in R445H patient-derived RGCs. The findings suggest a mechanism in which primary defects in mitochondrial network dynamics disrupt core mitochondrial functions, including bioenergetics, calcium homeostasis, and opening of the permeability transition pore, which may contribute to vision loss in DOA patients.

Keywords: Calcium homeostasis; Dominant optic atrophy; Mitochondrial networks; Neurodegeneration; OPA1; Retinal ganglion cells; iPSCs

DOI: https://doi.org/10.1186/s40478-025-01942-z

Cell Calcium. 2025 Feb 07. pii: S0143-4160(25)00009-0. [Epub ahead of print]126 103000

Rapid quantification of intracellular calcium stores reveals effects of membrane micropeptides on SERCA function.

Jacob D Cunningham, Taylor A Phillips, Jaroslava Seflova, Ellen E Cho, Seth L Robia.

To determine how regulation of the sarco(endo)plasmic reticulum calcium ATPase (SERCA) affects the Ca2+ content of the endoplasmic reticulum (ER), we developed a ratiometric ER-localized Ca2+ indicator to rapidly quantify Ca2+ stores and assess SERCA function in live cells. This assay enables screening of membrane micropeptides and small molecules that modulate SERCA and Na+/K+-ATPase activity and may facilitate development of therapies that target cellular Ca2+ handling. Of the micropeptides tested, phospholamban (PLB) had the greatest degree of inhibition of SERCA, as measured by a decrease in ER Ca2+ content compared to control. Sarcolipin (SLN), endoregulin (ELN), and another-regulin (ALN) also decreased ER Ca2+ content, though less potently than PLB. We also investigated micropeptides that have been shown to have a positive effect on ER Ca2+ uptake. Dwarf open reading frame (DWORF), a positive modulator of SERCA activity, and phospholemman (PLM), an inhibitor of the Na+/K+-ATPase, both increased ER Ca2+ content compared to control. A superinhibitory variant of PLM, R70C, further increased ER Ca2+ load compared to wild type PLM. Overall, our findings indicate that the inhibitory potency of micropeptides is governed by their relative binding affinities to SERCA. This allows for finely tuned modulation of Ca2+ handling in different tissues based on differential expressions of micropeptide species. Understanding the contribution of each micropeptide to SERCA regulation may reveal novel strategies for therapeutic intervention in conditions where calcium dysregulation plays a role, such as heart disease, vascular disease, or neurodegenerative disorders.

Keywords: Calcium signaling; Calcium transporter; Genetically-encoded calcium indicators; Micropeptides; SERCA

DOI: https://doi.org/10.1016/j.ceca.2025.103000

Mol Med Rep. 2025 Apr;pii: 91. [Epub ahead of print]31(4):

Potential of lactylation as a therapeutic target in cancer treatment (Review).

Zhengfeng Zhu, Xinzhe Zheng, Pengfei Zhao, Cheng Chen, Gang Xu, Xixian Ke.

Post‑translational modifications (PTMs) of proteins influence their functionality by altering the structure of precursor proteins. These modifications are closely linked to tumor progression through the regulation of processes such as cell proliferation, apoptosis, angiogenesis and invasion. Tumors produce large amounts of lactic acid through aerobic glycolysis. Lactic acid not only serves an important role in cell metabolism, but also serves an important role in cell communication. Lactylation, a PTM involving lactate and lysine residues as substrates, serves as an epigenetic regulator that modulates intracellular signaling, gene expression and protein function, thereby serving a crucial role in tumorigenesis and progression. The identification of lactylation provides a key breakthrough in elucidating the interaction between tumor metabolic reprogramming and epigenetic modification. The present review primarily summarizes the occurrence of lactylation, its effect on tumor progression, drug resistance, the tumor microenvironment and gut microbiota, and its potential as a therapeutic target for cancer. The aim of the present review was to provide novel strategies for potential cancer therapies.

Keywords: lactylation; post‑translational modification; therapeutic target; tumor

DOI: https://doi.org/10.3892/mmr.2025.13456

Ann Surg Treat Res. 2025 Feb;108(2): 108-123

Synergistic anticancer effects of mitochondria-targeting peptide combined with paclitaxel in breast cancer cells: a preclinical study.

Juneyoung Ahn, Ok-Hee Kim, Seongeon Jin, Ja-Hyoung Ryu, Dosang Lee, Woo-Chan Park, Say-June Kim.

Purpose: Mitochondria-accumulating amphiphilic peptide (Mito-FF) was designed to selectively target mitochondria in cancer cells and enhance anticancer effects through its unique structure. Mito-FF consists of (1) diphenylalanine, a β-sheet-forming building block critical for self-assembly; (2) triphenylphosphonium, a mitochondrial targeting moiety guiding the peptide to mitochondria; and (3) pyrene, a fluorescent probe enabling visualization of its accumulation and self-assembly. This study evaluates the anticancer efficacy of Mito-FF in breast cancer cells and explores its combination with paclitaxel, a standard therapy for breast cancer, focusing on its modulation of the epithelial-mesenchymal transition (EMT) pathway.
Methods: In vitro and in vivo experiments were performed using MCF-7 and MDA-MB-231 breast cancer cell lines and their respective xenograft models. Cell viability, migration, EMT marker expression, and apoptosis-related proteins were analyzed.
Results: Mito-FF demonstrated superior inhibition of cell viability and migration compared to paclitaxel alone in both cell lines. Combination therapy with Mito-FF and paclitaxel resulted in enhanced reduction of cell viability and migration. EMT markers were significantly modulated, with decreased mesenchymal markers (Snail and vimentin) and increased epithelial marker (E-cadherin) following combination treatment. Furthermore, the combination therapy synergistically elevated pro-apoptotic markers such as poly (adenosine diphosphate-ribose) polymerase and reduced anti-apoptotic markers such as myeloid cell leukemia 1. In vivo experiments revealed a marked reduction in tumor volume with combination therapy, accompanied by the highest expression levels of E-cadherin and pro-apoptotic marker Bim.
Conclusion: Mito-FF, designed for mitochondrial targeting and visualization, exhibited potent anticancer effects when combined with paclitaxel, in the breast cancer cells.

Keywords: Breast neoplasms; Epithelial-mesenchymal transition; Mito-FF; Paclitaxel; Triple negative breast neoplasms

DOI: https://doi.org/10.4174/astr.2025.108.2.108

Mol Oncol. 2025 Feb 07.

Etoposide-induced cancer cell death: roles of mitochondrial VDAC1 and calpain, and resistance mechanisms.

Aditya Karunanithi Nivedita, Varda Shoshan-Barmatz.

Etoposide is an inhibitor of DNA topoisomerase II, an enzyme essential for DNA transcription, replication, and chromosome segregation. It is well accepted that etoposide triggers cell death due to DNA damage. Our results indicate that multiple molecular mechanisms contribute to etoposide-induced apoptosis, including the overexpression of the mitochondrial voltage-dependent anion channel 1 (VDAC1) and its oligomerization, forming a mega-channel that releases pro-apoptotic proteins, thereby activating apoptosis. Etoposide induces C-terminal truncation of VDAC1 (VDAC1-ΔC) via the proteolytic actions of calpain-1 and asparagine endopeptidase (AEP). A calpain-specific inhibitor effectively prevented etoposide-induced VDAC1-ΔC formation, apoptosis, and the nuclear translocation of apoptosis-inducing factor (AIF). Additionally, etoposide upregulates the expression levels of apoptosis regulators (p53, Bax, p21, AIF) and of the proteases calpain and AEP. Etoposide-induced apoptosis and VDAC1 truncation are cell-type dependent and associated with calpain levels and activity. Etoposide-induced VDAC1-ΔC formation and apoptosis are tightly linked: as both display similar patterns of concentration- and time-dependence, both are inhibited by calpain and AEP inhibitors, as well as the VDAC1 oligomerization inhibitor VBIT-4, and are dependent on intracellular Ca2+. These findings highlight the complexity of etoposide's actions in different cellular contexts, suggest possible mechanisms of resistance, offer potential biomarkers for guiding etoposide treatment in cancer patients, and propose targeting VDAC1 and calpain as promising therapeutic strategies in cancer therapy.

Keywords: VDAC1; apoptosis; calpain; etoposide; mitochondria; topoisomerase inhibitors

DOI: https://doi.org/10.1002/1878-0261.13807