bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2024–08–11
three papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool



  1. Front Pharmacol. 2024 ;15 1428242
      The various roles of the mitochondria and the microbiome in health and disease have been thoroughly investigated, though they are often examined independently and in the context of chronic disease. However, the mitochondria and microbiome are closely connected, namely, through their evolution, maternal inheritance patterns, overlapping role in many diseases and their importance in the maintenance of human health. The concept known as the "mitochondria-microbiome crosstalk" is the ongoing bidirectional crosstalk between these two entities and warrants further exploration and consideration, especially in the context of primary mitochondrial disease, where mitochondrial dysfunction can be detrimental for clinical manifestation of disease, and the role and composition of the microbiome is rarely investigated. A potential mechanism underlying this crosstalk is the role of metabolites from both the mitochondria and the microbiome. During digestion, gut microbes modulate compounds found in food, which can produce metabolites with various bioactive effects. Similarly, mitochondrial metabolites are produced from substrates that undergo biochemical processes during cellular respiration. This review aims to provide an overview of current literature examining the mitochondria-microbiome crosstalk, the role of commonly studied metabolites serve in signaling and mediating these biochemical pathways, and the impact diet has on both the mitochondria and the microbiome. As a final point, this review highlights the up-to-date implications of the mitochondria-microbiome crosstalk in mitochondrial disease and its potential as a therapeutic tool or target.
    Keywords:  diet; microbiome; mitochondria; mitochondria-microbiome crosstalk; mitochondrial disease
    DOI:  https://doi.org/10.3389/fphar.2024.1428242
  2. Acta Pharmacol Sin. 2024 Aug 08.
      Mitochondria and the endoplasmic reticulum (ER) are vital organelles that influence various cellular physiological and pathological processes. Recent evidence shows that about 5%-20% of the mitochondrial outer membrane is capable of forming a highly dynamic physical connection with the ER, maintained at a distance of 10-30 nm. These interconnections, known as MAMs, represent a relatively conserved structure in eukaryotic cells, acting as a critical platform for material exchange between mitochondria and the ER to maintain various aspects of cellular homeostasis. Particularly, ER-mediated Ca2+ release and recycling are intricately associated with the structure and functionality of MAMs. Thus, MAMs are integral in intracellular Ca2+ transport and the maintenance of Ca2+ homeostasis, playing an essential role in various cellular activities including metabolic regulation, signal transduction, autophagy, and apoptosis. The disruption of MAMs observed in certain pathologies such as cardiovascular and neurodegenerative diseases as well as cancers leads to a disturbance in Ca2+ homeostasis. This imbalance potentially aggravates pathological alterations and disease progression. Consequently, a thorough understanding of the link between MAM-mediated Ca2+ transport and these diseases could unveil new perspectives and therapeutic strategies. This review focuses on the changes in MAMs function during disease progression and their implications in relation to MAM-associated Ca2+ transport.
    Keywords:  Ca2+ homeostasis; cancer; cardiovascular diseases; mitochondria-associated ER membranes; neurodegenerative diseases
    DOI:  https://doi.org/10.1038/s41401-024-01359-9
  3. Biochem Pharmacol. 2024 Aug 06. pii: S0006-2952(24)00452-0. [Epub ahead of print] 116469
      Due to the relevance of lactic acidosis in cancer, several therapeutic strategies have been developed targeting its production and/or regulation. In this matter, inhibition approaches of key proteins such as lactate dehydrogenase or monocarboxylate transporters have showed promising results, however, metabolic plasticity and tumor heterogeneity limits their efficacy. In this study, we explored the anticancer potential of a new strategy based on disturbing lactate permeability independently of monocarboxylate transporters activity using a small molecule ionophore named Lactrans-1. Derived from click-tambjamines, Lactrans-1 facilitates transmembrane lactate transportation in liposome models and reduces cancer cell viability. The results showed that Lactrans-1 triggered both apoptosis and necrosis depending on the cell line tested, displaying a synergistic effect in combination with first-line standard chemotherapeutic cisplatin. The ability of this compound to transport outward lactate anions was confirmed in A549 and HeLa cells, two cancer cell lines having distinct rates of lactate production. In addition, through cell viability reversion experiments it was possible to establish a correlation between the amount of lactate transported and the cytotoxic effect exhibited. The movement of lactate anions was accompanied with intracellular pH disturbances that included basification of lysosomes and acidification of the cytosol and mitochondria. We also observed mitochondrial swelling, increased ROS production and activation of oxidative stress signaling pathways p38-MAPK and JNK/SAPK. Our findings provide evidence that enhancement of lactate permeability is critical for cellular pH homeostasis and effective to trigger cancer cell death, suggesting that Lactrans-1 may be a promising anticancer therapy.
    Keywords:  Anionophores; Cancer metabolism; Click-tambjamines; Lactate; Small molecules; pH deregulation
    DOI:  https://doi.org/10.1016/j.bcp.2024.116469