Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the cell and mitochondrial membrane potentials, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this Review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes, and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

/pdf/mitochondria-targeted-triphenylphosphonium-based-compounds-4xqo2evab5.pdf

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Ferroptosis is a new type of oxidative regulated cell death (RCD) driven by iron-dependent lipid peroxidation. As major sites of iron utilization and master regulators of oxidative metabolism, mitochondria are the main source of reactive oxygen species (ROS) and, thus, play a role in this type of RCD. Ferroptosis is, indeed, associated with severe damage in mitochondrial morphology, bioenergetics, and metabolism. Furthermore, dysregulation of mitochondrial metabolism is considered a biochemical feature of neurodegenerative diseases linked to ferroptosis. Whether mitochondrial dysfunction can, per se, initiate ferroptosis and whether mitochondrial function in ferroptosis is context-dependent are still under debate. Cancer cells accumulate high levels of iron and ROS to promote their metabolic activity and growth. Of note, cancer cell metabolic rewiring is often associated with acquired sensitivity to ferroptosis. This strongly suggests that ferroptosis may act as an adaptive response to metabolic imbalance and, thus, may constitute a new promising way to eradicate malignant cells. Here, we review the current literature on the role of mitochondria in ferroptosis, and we discuss opportunities to potentially use mitochondria-mediated ferroptosis as a new strategy for cancer therapy.

Ferroptosis and Cancer: Mitochondria Meet the “Iron Maiden” Cell Death

Reactive oxygen species (ROS) are essential for life and are involved in the regulation of almost all biological processes. ROS production is critical for plant development, response to abiotic stresses and immune responses. Here, we focus on recent discoveries in ROS biology emphasizing abiotic and biotic stress responses. Recent advancements have resulted in the identification of one of the first sensors for extracellular ROS and highlighted waves of ROS production during stress signalling in Arabidopsis. Enzymes that produce ROS, including NADPH oxidases, exhibit precise regulation through diverse post-translational modifications. Discoveries highlight the importance of both amino- and carboxy-terminal regulation of NADPH oxidases through protein phosphorylation and cysteine oxidation. Here, we discuss advancements in ROS compartmentalization, systemic ROS waves, ROS sensing and post-translational modification of ROS-producing enzymes and identify areas where foundational gaps remain. This Review covers the recent advancements in our understanding of reactive oxygen species production, regulation and perception in plants. It is primarily focused on stress responses and the role of NADPH oxidases.

Stress-induced reactive oxygen species compartmentalization, perception and signalling

Background Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1911481?articleTools=true

Soluble Urokinase Receptor and Acute Kidney Injury

Trained immunity is a functional state of the innate immune response and is characterized by long-term epigenetic reprogramming of innate immune cells. This concept originated in the field of infectious diseases - training of innate immune cells, such as monocytes, macrophages and/or natural killer cells, by infection or vaccination enhances immune responses against microbial pathogens after restimulation. Although initially reported in circulating monocytes and tissue macrophages (termed peripheral trained immunity), subsequent findings indicate that immune progenitor cells in the bone marrow can also be trained (that is, central trained immunity), which explains the long-term innate immunity-mediated protective effects of vaccination against heterologous infections. Although trained immunity is beneficial against infections, its inappropriate induction by endogenous stimuli can also lead to aberrant inflammation. For example, in systemic lupus erythematosus and systemic sclerosis, trained immunity might contribute to inflammatory activity, which promotes disease progression. In organ transplantation, trained immunity has been associated with acute rejection and suppression of trained immunity prolonged allograft survival. This novel concept provides a better understanding of the involvement of the innate immune response in different pathological conditions, and provides a new framework for the development of therapies and treatment strategies that target epigenetic and metabolic pathways of the innate immune system. 

/pdf/trained-immunity-basic-concepts-and-contributions-to-1i3dxh12.pdf

Trained immunity — basic concepts and contributions to immunopathology

MitoSOX-based assays are widely used to detect mitochondrial reactive oxygen species (ROS), especially superoxide. To this end, 5 µM MitoSOX is commonly used. In this ROS Protocols article, we described the flow cytometric protocol involving the use of various concentrations of MitoSOX (1, 2.5, 5 µM) for detecting mitochondrial ROS in control and mitochondrial DNA-deficient (MD) melanoma B16-F10 cells. We also compared the MitoSOX-based flow cytometry with lucigenin-derived chemiluminometry for their ability to reliably detect the relative differences in mitochondrial ROS formation in the control and MD cells. Our results suggested that 1 µM, rather than the commonly used 5 µM, appeared to be the optimal concentration of MitoSOX for detecting mitochondrial ROS via flow cytometry.

/pdf/mitosox-based-flow-cytometry-for-detecting-mitochondrial-ros-5abw8md8p4.pdf

MitoSOX-Based Flow Cytometry for Detecting Mitochondrial ROS

Detection and measurement of doxorubicin in biological systems, including body fluids, cells, and tissues, are instrumental in understanding the mechanisms of action of this widely used drug in treating cancer as well as in causing adverse effects. In this article, we, for the first time, characterized the use of fluorescence-based techniques, including fluorescence spectrometry, microscopy, and flow cytometry in measuring and/or detecting doxorubicin in biological systems, including cell lysates and cultured intact cells. We showed that doxorubicin has a maximum excitation and emission wavelength of 470 and 560 nm, respectively. The detection sensitivity by fluorescence spectrometry is less than 0.1 µM in buffers and cell lysates. Fluorescence microscopy demonstrated the readily detection of concentration-dependent accumulation of doxorubicin in cultured cells via either green or red fluorescence, but with green fluorescence showing a higher sensitivity of detection. Flow cytometry also revealed sensitive detection of doxorubicin accumulation in cell suspensions in a concentration-dependent manner. The readily and sensitive measurement and detection of doxorubicin by the above three fluorescence-based techniques has important implications in studying the cellular dynamics of doxorubicin in both cancer and normal cells under various experimental conditions.

/pdf/fluorescence-based-assays-for-measuring-doxorubicin-in-4qb3x2i0xq.pdf

Fluorescence-Based Assays for Measuring Doxorubicin in Biological Systems.

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MitoSOX-Based Flow Cytometry for Detecting Mitochondrial ROS

Fluorescence-Based Assays for Measuring Doxorubicin in Biological Systems.