bims-miptne 2024-10-06 papers

Mitochondrion. 2024 Sep 30. pii: S1567-7249(24)00129-6. [Epub ahead of print] 101971

Targeting mitochondria with small molecules: A promising strategy for combating Parkinson's disease.

Parkinson's disease (PD), a neurodegenerative disorder, is one of the most significant challenges confronting modern societies, affecting millions of patients globally each year. The pathophysiology of PD is significantly influenced by mitochondrial dysfunction, as evident by the contribution of altered mitochondrial dynamics, bioenergetics, and increased oxidative stress to neuronal death. This review examines the potential use of small molecules that target mitochondria as a therapeutic approach for treating PD. Progress in mitochondrial biology has revealed various mitochondrial targets that can be modulated to restore function and mitigate neurodegeneration. Small molecules that promote mitochondrial biogenesis, enhance mitochondrial dynamics, decrease oxidative stress, and prevent the opening of the mitochondrial permeability transition pore (mPTP) have shown promise in preclinical models. Additionally, targeting mitochondrial quality control mechanisms, such as mitophagy, provides another therapeutic approach. This review explores recent research on small molecules targeting mitochondria, examines their mechanisms of action, and assesses their potential efficacy and safety profiles. By highlighting the most promising candidates and addressing the challenges and future directions in this field, this review aims to offer a comprehensive overview of current and future prospects for mitochondrial-targeted therapies in PD. Ultimately, treating mitochondrial dysfunction holds significant promise for developing disease-modifying PD medications, giving patients hope for better outcomes and improved quality of life.

Keywords: Mitochondrial dysfunction; Oxidative Stress; Parkinson’s disease; Reactive oxygen species; Small molecule

DOI: https://doi.org/10.1016/j.mito.2024.101971

Cell Rep. 2024 Sep 28. pii: S2211-1247(24)01145-8. [Epub ahead of print]43(10): 114794

Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.

Gan Zhao, Mingkang Jia, Shicong Zhu, He Ren, Guopeng Wang, Guangwei Xin, Mengjie Sun, Xiangyang Wang, Qiaoyu Lin, Qing Jiang, Chuanmao Zhang.

Cell division is tightly regulated and requires an expanded energy supply. However, how this energy is generated remains unclear. Here, we establish a correlation between two mitochondrial Ca2+ influx events and ATP production during mitosis. While both events promote ATP production during mitosis, the second event, the Ca2+ influx surge, is substantial. To facilitate this Ca2+ influx surge, the lamin B receptor (LBR) organizes a mitosis-specific endoplasmic reticulum (ER)-mitochondrial contact site (ERMCS), creating a rapid Ca2+ transport pathway. LBR acts as a tether, connecting the ER Ca2+ release channel IP3R with the mitochondrial VDAC2. Depletion of LBR disrupts the Ca2+ influx surge, reduces ATP production, and postpones the metaphase-anaphase transition and subsequent cell division. These findings provide insight into the mechanisms underlying mitotic energy production and supply required for cell proliferation.

Keywords: CP: Cell biology; CP: Metabolism; Ca(2+); ER-mitochondrial contact; LBR; VDAC2; cell cycle; cell division; energy generation; metaphase-anaphase transition; mitochondria; mitosis

DOI: https://doi.org/10.1016/j.celrep.2024.114794

Biomolecules. 2024 Sep 15. pii: 1159. [Epub ahead of print]14(9):

ANT-Mediated Inhibition of the Permeability Transition Pore Alleviates Palmitate-Induced Mitochondrial Dysfunction and Lipotoxicity.

Natalia V Belosludtseva, Anna I Ilzorkina, Dmitriy A Serov, Mikhail V Dubinin, Eugeny Yu Talanov, Maxim N Karagyaur, Alexandra L Primak, Jiankang Liu, Konstantin N Belosludtsev.

Hyperlipidemia is a major risk factor for vascular lesions in diabetes mellitus and other metabolic disorders, although its basis remains poorly understood. One of the key pathogenetic events in this condition is mitochondrial dysfunction associated with the opening of the mitochondrial permeability transition (MPT) pore, a drop in the membrane potential, and ROS overproduction. Here, we investigated the effects of bongkrekic acid and carboxyatractyloside, a potent blocker and activator of the MPT pore opening, respectively, acting through direct interaction with the adenine nucleotide translocator, on the progression of mitochondrial dysfunction in mouse primary lung endothelial cells exposed to elevated levels of palmitic acid. Palmitate treatment (0.75 mM palmitate/BSA for 6 days) resulted in an 80% decrease in the viability index of endothelial cells, which was accompanied by mitochondrial depolarization, ROS hyperproduction, and increased colocalization of mitochondria with lysosomes. Bongkrekic acid (25 µM) attenuated palmitate-induced lipotoxicity and all the signs of mitochondrial damage, including increased spontaneous formation of the MPT pore. In contrast, carboxyatractyloside (10 μM) stimulated cell death and failed to prevent the progression of mitochondrial dysfunction under hyperlipidemic stress conditions. Silencing of gene expression of the predominate isoform ANT2, similar to the action of carboxyatractyloside, led to increased ROS generation and cell death under conditions of palmitate-induced lipotoxicity in a stably transfected HEK293T cell line. Altogether, these results suggest that targeted manipulation of the permeability transition pore through inhibition of ANT may represent an alternative approach to alleviate mitochondrial dysfunction and cell death in cell culture models of fatty acid overload.

Keywords: MPT pore; adenylate translocator; bongkrekic acid; carboxyatractyloside; lipotoxity; mitochondria; oxidative stress; palmitate

DOI: https://doi.org/10.3390/biom14091159

Cancer Metastasis Rev. 2024 Oct 01.

Mitochondrial ribosomal proteins in metastasis and their potential use as prognostic and therapeutic targets.

Jasmine M Bacon, Johanna L Jones, Guei-Sheung Liu, Joanne L Dickinson, Kelsie Raspin.

The mitochondrion is an essential cell organelle known as the powerhouse of the cell. Mitochondrial ribosomal proteins (MRPs) are nuclear encoded, synthesised in the cytoplasm but perform their main functions in the mitochondria, which includes translation, transcription, cell death and maintenance. However, MRPs have also been implicated in cancer, particularly advanced disease and metastasis across a broad range of cancer types, where they play a central role in cell survival and progression. For some, their altered expression has been investigated as potential prognostic markers, and/or therapeutic targets, which is the focus of this review. Several therapies targeting MRPs are currently approved by the Food and Drug Administration and the European Medicines Agency for use in other diseases, revealing the opportunity for repurposing their use in advanced and metastatic cancer. Herein, we review the evidence supporting key MRPs as molecular drivers of advanced disease in multiple cancer types. We also highlight promising avenues for future use of MRPs as precision targets in the treatment of late-stage cancers for which there are currently very limited effective treatment options.

Keywords: Cancer; Metastasis; Mitochondrial ribosomal proteins; Prognostic targets; Therapeutic targets

DOI: https://doi.org/10.1007/s10555-024-10216-4