bims-miptne 2025-04-27 papers

Arch Razi Inst. 2024 Aug;79(4): 805-814

Antioxidative Potential and Activity of Potassium Polyacrylate and Coenzyme Q10 on Rat Hepatic Mitochondrial Permeability Transition Pores.

A O Adeoye, J O Olanlokun, D J Porta, J O Akinyelu, M A Rivoira, N H Garcia.

Multiple biological activities of coenzyme Q10 have been demonstrated, opening up opportunities for research and development. However, the biological action of potassium polyacrylate and its effect on the mitochondrial permeability transition pores are both poorly understood. Therefore, this study investigated the in vitro antioxidative potential of potassium polyacrylate (PCK) and coenzyme Q10 (CoQ10) and their effects on mitochondrial permeability transition pores. In vitro antioxidant and angiotensin-converting enzyme inhibitory activities were assessed using standard methods, and lipid peroxidation was also determined. Mitochondrial swelling was evaluated as the change in absorbance under succinate-energized conditions. Cytochrome c release and mitochondrial ATPase activity were assessed. The results showed that PCK and CoQ10 significantly scavenged DPPH and nitric oxide radicals in a concentration-dependent manner and demonstrated a better ferricreducing antioxidant potential. PCK exhibited a high DPPH radical scavenging ability with the lowest IC50 value of 54.05 µg/mL while CoQ10 exhibited higher reducing power with the IC50 value of 82.14 µg/mL.Both were also found to inhibit angiotensin-converting enzyme activity. In addition, PCK and CoQ10 significantly (p<0.05) prevented lipid peroxidation, modulated the opening of mitochondrial permeability transition (mPT) pores and caused no significant release of cytochrome c. However, CoQ10 showed a mild inductive effect on mPT pores at higher concentrations. PCK and CoQ10 also increased mitochondrial ATPase activity. The results of this study suggest that both PCK and CoQ10 may be helpful in the treatment of diseases such as neurological disorders where excessive apoptosis is associated with excessive tissue degradation.

Keywords: Antioxidants; Coenzyme Q10; Mitochondrial Permeability Transition, Apoptosis; Potassium Polyacrylate

DOI: https://doi.org/10.32592/ARI.2024.79.4.805

Nat Nanotechnol. 2025 Apr 23.

An orally administered gene editing nanoparticle boosts chemo-immunotherapy in colorectal cancer.

Kai Zhao, Yu Yan, Xiao-Kang Jin, Ting Pan, Shi-Man Zhang, Chi-Hui Yang, Zhi-Yong Rao, Xian-Zheng Zhang.

Chemoresistance and immunosuppression are common obstacles to the efficacy of chemo-immunotherapy in colorectal cancer (CRC) and are regulated by mitochondrial chaperone proteins. Here we show that the disruption of the tumour necrosis factor receptor-associated protein 1 (TRAP1) gene, which encodes a mitochondrial chaperone in tumour cells, causes the translocation of cyclophilin D in tumour cells. This process results in the continuous opening of the mitochondrial permeability transition pore, which enhances chemotherapy-induced cell necrosis and promotes immune responses. On the basis of this discovery we developed an oral CRISPR-Cas9 delivery system based on zwitterionic and polysaccharide polymer-coated nanocomplexes that disrupts the TRAP1 gene in CRC. This system penetrates the intestinal mucus layer and undergoes epithelial transcytosis, accumulating in CRC tissues. It enhances chemotherapeutic efficacy by overcoming chemoresistance and activating the tumour immune microenvironment in orthotopic, chemoresistant and spontaneous CRC models, with remarkable synergistic antitumour effects. This oral CRISPR-Cas9 delivery system represents a promising therapeutic strategy for the clinical management of CRC.

DOI: https://doi.org/10.1038/s41565-025-01904-5

Mitochondrion. 2025 Apr 18. pii: S1567-7249(25)00039-X. [Epub ahead of print] 102042

Mitochondrial transplantation: Triumphs, challenges, and impacts on nuclear genome remodelling.

Elly H Shin, Quinn Le, Rachel Barboza, Amanda Morin, Shiva M Singh, Christina A Castellani.

Mitochondria are membrane-bound organelles of eukaryotic cells that play crucial roles in cell functioning and homeostasis, including ATP generation for cellular energy. Mitochondrial function is associated with several complex diseases and disorders, including cardiovascular, cardiometabolic, neurodegenerative diseases and some cancers. The risk for these diseases and disorders is often associated with mitochondrial dysfunction, particularly the quantitative and qualitative features of the mitochondrial genome. Emerging results implicate mito-nuclear crosstalk as the mechanism by which mtDNA variation affects complex disease outcomes. Experimental approaches are emerging for the targeting of mitochondria as a potential therapeutic for several of these diseases, particularly in the form of mitochondrial transplantation. Current approaches to mitochondrial transplantation generally involve isolating healthy mitochondria from donor cells and introducing them to diseased recipients towards amelioration of mitochondrial dysfunction. Using such a protocol, several reports have shown recovery of mitochondrial function and improved disease outcomes post-mitochondrial transplantation, highlighting its potential as a therapeutic method for several complex, severe and debilitating diseases. Additionally, the mitochondrial genome can be modified prior to transplantation to target disease-associated site-specific mutations and to reduce the ratio of mutant-to-WT alleles. These promising results may underlie the potential impact of mitochondrial transplantation on mito-nuclear genome interactions in the setting of the disease. Further, we recommend that mitochondrial transplantation experimentation include an assessment of potential impacts on remodelling of the nuclear genome, particularly the nuclear epigenome and transcriptome. Herein, we review these and other triumphs and challenges of mitochondrial transplantation as a potential novel therapeutic for mitochondria-associated diseases.

Keywords: Mito-nuclear crosstalk; Mitochondria; Mitochondrial DNA; Mitochondrial transplantation; Nuclear epigenome; Nuclear transcriptome

DOI: https://doi.org/10.1016/j.mito.2025.102042

Nat Cell Biol. 2025 Apr 21.

Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.

Nicotinamide adenine dinucleotide phosphate (NADPH) is a vital electron donor essential for macromolecular biosynthesis and protection against oxidative stress. Although NADPH is compartmentalized within the cytosol and mitochondria, the specific functions of mitochondrial NADPH remain largely unexplored. Here we demonstrate that NAD+ kinase 2 (NADK2), the principal enzyme responsible for mitochondrial NADPH production, is critical for maintaining protein lipoylation, a conserved lipid modification necessary for the optimal activity of multiple mitochondrial enzyme complexes, including the pyruvate dehydrogenase complex. The mitochondrial fatty acid synthesis (mtFAS) pathway utilizes NADPH for generating protein-bound acyl groups, including lipoic acid. By developing a mass-spectrometry-based method to assess mammalian mtFAS, we reveal that NADK2 is crucial for mtFAS activity. NADK2 deficiency impairs mtFAS-associated processes, leading to reduced cellular respiration and mitochondrial translation. Our findings support a model in which mitochondrial NADPH fuels the mtFAS pathway, thereby sustaining protein lipoylation and mitochondrial oxidative metabolism.

DOI: https://doi.org/10.1038/s41556-025-01655-4