bims-miptne 2024-10-20 papers

Methods Mol Biol. 2025 ;2861 155-164

Analyzing Mitochondrial Calcium Influx in Isolated Mitochondria.

Mitochondria play a crucial role in Ca2+ signaling and homeostasis and can contribute to shaping the cytosolic Ca2+ landscape as well as regulate a variety of pathways including energy production and cell death. Dysregulation of mitochondrial Ca2+ homeostasis promotes pathologies including neurodegenerative diseases, cardiovascular disorders, and metabolic syndromes. The significance of mitochondria to Ca2+ signaling and regulation underscores the value of methods to assess mitochondrial Ca2+ import. Here we present a plate reader-based method using the Ca2+-sensitive fluorescent probe calcium green-5 N to measure mitochondrial Ca2+ import in isolated cardiac mitochondria. This technique can be expanded to measure Ca2+ uptake in mitochondria isolated from other tissue types and from cultured cells.

Keywords: Calcium; Heart; Mitochondria; Mitochondrial permeability transition pore; Signaling; Uniporter

DOI: https://doi.org/10.1007/978-1-0716-4164-4_12

Trends Pharmacol Sci. 2024 Oct 14. pii: S0165-6147(24)00209-8. [Epub ahead of print]

MICUs protect the heart by regulating mitochondrial calcium.

Ulas Ozkurede, Shanmugasundaram Pakkiriswami, Julia C Liu.

Regulation of mitochondrial calcium uptake by the mitochondrial calcium uniporter (mtCU) complex is crucial for heart function. In a recent study, Hasan et al. demonstrated that mitochondrial calcium uptake (MICU)1 and MICU2, regulatory subunits of the complex, help maintain calcium homeostasis in cardiac mitochondria, providing potential targets for therapies aimed at improving mitochondrial function in heart disease.

Keywords: EMRE; MCU; MICU1; MICU2; calcium; heart; mitochondria

DOI: https://doi.org/10.1016/j.tips.2024.09.010

bioRxiv. 2024 Oct 08. pii: 2024.10.07.617073. [Epub ahead of print]

Direct mitochondrial import of lactate supports resilient carbohydrate oxidation.

Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate is an important energy source for many organs, but first must be oxidized to pyruvate for entry into the tricarboxylic acid cycle (TCA cycle). This reaction is thought to occur in the cytosol, with pyruvate subsequently transported into mitochondria via the mitochondrial pyruvate carrier (MPC). Using 13 C stable isotope tracing, we demonstrated that lactate is oxidized in the myocardial tissue of mice even when the MPC is genetically deleted. This MPC-independent lactate import and mitochondrial oxidation is dependent upon the monocarboxylate transporter 1 (MCT1/ Slc16a1 ). Mitochondria isolated from the myocardium without MCT1 exhibit a specific defect in mitochondrial lactate, but not pyruvate, metabolism. The import and subsequent mitochondrial oxidation of lactate by mitochondrial lactate dehydrogenase (LDH) acts as an electron shuttle, generating sufficient NADH to support respiration even when the TCA cycle is disrupted. In response to diverse cardiac insults, animals with hearts lacking MCT1 undergo rapid progression to heart failure with reduced ejection fraction. Thus, the mitochondrial import and oxidation of lactate enables carbohydrate entry into the TCA cycle to sustain cardiac energetics and maintain myocardial structure and function under stress conditions.

DOI: https://doi.org/10.1101/2024.10.07.617073

Stem Cell Rev Rep. 2024 Oct 18.

Mitochondria's Role in the Maintenance of Cancer Stem Cells in Hepatocellular Carcinoma.

Manar A Elhinnawi, Michael Ibrahim Boushra, Donia Mohamed Hussien, Fatema Hesham Hussein, Islam Ahmed Abdelmawgood.

Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and is recognized as a major contributor to cancer-related mortality worldwide. Cancer stem cells (CSCs) are a tiny group of cancer cells that possess a significant ability to regenerate themselves, form tumors, and undergo differentiation. CSCs have a pivotal role in the initiation, spread, recurrence, and resistance to treatment of cancer. As a result, they are very susceptible to being targeted for therapeutic intervention. The potential to cure HCC may be achieved by efficiently targeting drugs that eradicate cancer stem cells. Mitochondria have a crucial function in granting drug resistance to cancer stem cells by means of mitochondrial metabolism, biogenesis, and dynamics. Dysfunction in mitochondrial metabolic processes, such as mitochondrial oxidative phosphorylation (OXPHOS), calcium signaling, and reactive oxygen species (ROS) generation, contributes to the initiation and progression of human malignancies, including HCC. ROS have both beneficial and detrimental effects depending on their concentration. Consequently, ROS have become a prominent subject in the study of the fundamental mechanisms of HCC. Furthermore, an imbalance in the process of creating new mitochondria is a characteristic feature of CSCs, and an increase in mitochondrial biogenesis is associated with the heightened resistance observed in CSCs. This article provides a detailed examination of the involvement of mitochondria in the preservation of CSCs, as well as the spread of HCC. A deeper understanding of how mitochondria participate in tumorigenesis and drug resistance could result in the discovery of novel cancer treatments.

Keywords: Cancer; Cancer stem cell; Hepatocellular carcinoma; Mitochondria; Mitophagy

DOI: https://doi.org/10.1007/s12015-024-10797-1