bims-miptne 2024-12-29 papers

Biomed Pharmacother. 2024 Dec 20. pii: S0753-3322(24)01653-6. [Epub ahead of print]182 117767

Inhibition of the mitochondrial permeability transition pore as a promising target for protecting auditory function in cisplatin-induced hearing loss.

Ye-Ri Kim, Sujin Jun, Sunhwa Jung, Byeonghyeon Lee, Sang-Hee Lee, Jaehyuk Lee, Jong-Su Hwang, Themis Thoudam, Hoyul Lee, Ibotombi Singh Sinam, Jae-Han Jeon, Kyu-Yup Lee, Sun-Joon Min, Un-Kyung Kim.

mPTP is a multi-protein complex that opens in mitochondria during cell death. Cisplatin-induced hearing loss is also known to be caused by mPTP opening. Thus, our study evaluated the protective effect of a novel mPTP inhibitor named DBP-iPT against cisplatin-induced hearing loss. The cell viability result showed that DBP-iPT provided a 40 % protective effect compared to the group treated with cisplatin. In addition, the DBP-iPT treated group exhibited a reduction in intracellular ROS levels, counteracting the excessive ROS accumulation induced by cisplatin at the whole cell level. Intriguingly, mitochondrial ROS levels in the DBP-iPT group were elevated three-fold compared to the cisplatin-treated group. Despite this increase in mitochondrial ROS, the mitochondrial membrane potential in the DBP-iPT group was three times higher than that of the control. These findings present intriguing contradictions to prior studies. Therefore, we investigated whether the mitochondria were damaged or not and found that DBP-iPT treatment maintained an increased portion of elongated mitochondria, suggesting autophagy-mediated removal of damaged mitochondria. This process leads to improved mitochondrial dynamics. Finally, in vivo studies confirmed that the ABR test using a mouse model showed the same pattern of protection against cisplatin-induced hearing loss in the DBP-iPT treatment group. We have identified a new target that has a protective effect against cisplatin-induced hearing loss. Therefore, this study is expected to provide valuable insights as it focuses on targeting mPTP opening to protect against ototoxicity caused by cisplatin. This discovery will serve as a significant foundation for future research.

Keywords: Autophagy; Cisplatin; Hearing loss; Mitochondrial permeability transition pore; Reactive oxygen species

DOI: https://doi.org/10.1016/j.biopha.2024.117767

Muscle Nerve. 2024 Dec 23.

Cyclosporine A Delays the Terminal Disease Stage in the Tfam KO Mitochondrial Myopathy Mouse Model Without Improving Mitochondrial Energy Production.

Benjamin Chatel, Isabelle Varlet, Augustin C Ogier, Emilie Pecchi, Monique Bernard, Julien Gondin, Håkan Westerblad, David Bendahan, Charlotte Gineste.

INTRODUCTION AND AIMS: Mitochondrial myopathies are rare genetic disorders for which no effective treatment exists. We previously showed that the pharmacological cyclophilin inhibitor cyclosporine A (CsA) extends the lifespan of fast-twitch skeletal muscle-specific mitochondrial transcription factor A knockout (Tfam KO) mice, lacking the ability to transcribe mitochondrial DNA and displaying lethal mitochondrial myopathy. Our present aim was to assess whether the positive effect of CsA was associated with improved in vivo mitochondrial energy production.
METHODS: Mice were treated with CsA for 4 weeks, beginning at 12 weeks (i.e., before the terminal disease phase). Hindlimb plantar flexor muscles were fatigued by 80 contractions (40 Hz, 1.5 s on, 6 s off) while measuring force and energy metabolism using phosphorus-31 magnetic resonance spectroscopy.
RESULTS: Force decreased at similar rates in Tfam KO mice with and without the CsA treatment, reaching 50% of the baseline value after ~14 ± 1 contractions, which was faster than in control mice (25 ± 1 contractions). Phosphocreatine (PCr) decreased to ~10% of the control concentration in Tfam KO mice, independent of the treatment, which was larger than the ~20% observed in control mice. The time constant of PCr recovery was higher in untreated Tfam KO than that in control muscle (+100%) and similar in untreated and CsA-treated Tfam KO mice.
DISCUSSION: The results do not support improved mitochondrial energy production as a mechanism underlying the prolonged lifespan of Tfam KO mitochondrial myopathy mice treated with CsA. Thus, other mechanisms must be involved, such as the previously observed CsA-mediated protection against excessive mitochondrial Ca2+ accumulation.

Keywords: force production; mitochondrial function; muscle disease; pharmacological agent; preclinical model

DOI: https://doi.org/10.1002/mus.28315

Metabolites. 2024 Dec 18. pii: 711. [Epub ahead of print]14(12):

The Mitochondrial Blueprint: Unlocking Secondary Metabolite Production.

Yang Li, Yujia Zhang, Xinyu He, Ziyi Guo, Ning Yang, Guohui Bai, Juanjuan Zhao, Delin Xu.

Mitochondrial metabolism plays a pivotal role in regulating the synthesis of secondary metabolites, which are crucial for the survival and adaptation of organisms. These metabolites are synthesized during specific growth stages or in response to environmental stress, reflecting the organism's ability to adapt to changing conditions. Mitochondria, while primarily known for their role in energy production, directly regulate secondary metabolite biosynthesis by providing essential precursor molecules, energy, and reducing equivalents necessary for metabolic reactions. Furthermore, they indirectly influence secondary metabolism through intricate signaling pathways, including reactive oxygen species (ROS), metabolites, and redox signaling, which modulate various metabolic processes. This review explores recent advances in understanding the molecular mechanisms governing mitochondrial metabolism and their regulatory roles in secondary metabolite biosynthesis, which highlights the involvement of transcription factors, small RNAs, and post-translational mitochondrial modifications in shaping these processes. By integrating current insights, it aims to inspire future research into mitochondrial regulatory mechanisms in Arabidopsis thaliana, Solanum tuberosum, Nicotiana tabacum, and others that may enhance their secondary metabolite production. A deeper understanding of the roles of mitochondria in secondary metabolism could contribute to the development of new approaches in biotechnology applications.

Keywords: biosynthesis; mitochondria; regulation mechanism; secondary metabolites; signaling pathway

DOI: https://doi.org/10.3390/metabo14120711

Neoplasia. 2024 Dec 26. pii: S1476-5586(24)00158-1. [Epub ahead of print]60 101117

Galectin-3 secreted by triple-negative breast cancer cells regulates T cell function.

Annat Raiter, Yael Barhum, Julia Lipovetsky, Chen Menachem, Sharona Elgavish, Shmuel Ruppo, Yehudit Birger, Shai Izraeli, Orna Steinberg-Shemer, Rinat Yerushalmi.

Triple-negative breast cancer (TNBC) is an aggressive subtype that accounts for 10-15 % of breast cancer. Current treatment of high-risk early-stage TNBC includes neoadjuvant chemo-immune therapy. However, the substantial variation in immune response prompts an urgent need for new immune-targeting agents. This requires a comprehensive understanding of TNBC's tumor microenvironment. We recently demonstrated that Galectin-3 (Gal-3) binding protein/Gal-3 complex secreted by TNBC cells induces immunosuppression, through inhibiting CD45 signaling in T cells. Here, we further investigated the interaction between secreted Gal-3 and T cells in TNBC. Using CRISPR/Cas9 gene editing of the TNBC MDA-MB-231 cell-line, we obtained Gal-3 negative(neg) clones. We studied these in an in-vitro model, co-cultured with peripheral blood mononuclear cells (PBMC) to imitate immune-tumor interaction, and in an in-vivo model, when implanted in mice. Gal-3neg tumors in mice had decelerated tumor growth after PBMC inoculation. In contrast, the Gal-3 positive(pos) tumors continued growing despite PBMC inoculation, and tumor T regulatory cell (CD4/FoxP3+) infiltration increased. RNA sequencing of T cells from women with TNBC with elevated plasma levels of Gal-3 revealed significantly lower expression of oxidative phosphorylation genes than in T cells from healthy women. Similarly, in our in-vitro model, the decreased expression of oxidative phosphorylation genes and mitochondrial dysfunction resulted in a significant increase in CD8 intracellular reactive oxygen species. Consequently, T exhausted cells (CD8/PD1/Tim3/Lag3+) significantly increased in PBMC co-cultured with Gal-3pos TNBCs. To conclude, we revealed a novel TNBC-related Gal-3 suppressor mechanism that involved upregulation of CD4 T regulatory and of CD8 T exhausted cells.

Keywords: Galectin-3; Oxidative phosphorylation; T exhausted cells; Triple negative breast cancer

DOI: https://doi.org/10.1016/j.neo.2024.101117