Researchers Tailor Blood Pressure Drug Delivery Directly to Cells’ ‘Power Plants’
Schematic illustration of the design, synthesis, and mechanism of uptake of the mitochondrially targeted Losartan.
News Release, World Mitochondria Society, Berlin - Germany – September 6, 2022
In a study using lab-grown cells, Johns Hopkins Medicine researchers specializing in aging report they have successfully delivered a common blood pressure drug directly to the inner membrane of mitochondria, the "power plants" in the cells of humans, animals, plants and most other organisms.
Developing ways to directly target these energy-producing parts of the cell for delivery of drugs has long been a goal for researchers because mitochondria drive, control or play a role in almost every biological process, including natural cell death and aging. Alterations or declines in mitochondrial activity and pathways are closely aligned with decreased organ function and frailty. But because of the mitochondria's double-membrane structure, scientists have found it challenging to get drug molecules to penetrate the inner membrane and gain access to the core functions of the organelles.
The new study, described in the Aug. 4 issue of PNAS nexus, reports on a method that essentially hijacks a system already used by mitochondria to transport oxygen and other chemicals to the inner membrane.
For the study, the researchers lab-synthesized three naturally occurring transport proteins that interact with mitochondria. They then fused a commonly prescribed blood pressure medication (losartan) to each of these three proteins to determine which had the highest success rate penetrating the inner membrane of the mitochondria. These fused proteins, dubbed mtLOS1, mtLOS2 and mtLOS3, when introduced to lab-grown cells in separate trials, were able to transport the drug directly to the mitochondria at a significantly higher concentration than was possible with free losartan not fused to the transport protein. This could be seen under a microscope using florescence.
In a proof of concept experiment, the researchers also tested a "scrambled" version of mtLOS, which was unable to penetrate the inner membrane.
Abadir says further research is needed, but the goal is to use mtLOS or other natural transport pathways to deliver medicines that directly and efficiently target the biochemical imbalances and losses linked to chronic inflammation and weakened organ function characteristic of aging and many disorders.
"We know people age in part because of mitochondrial decline, and scientists have been trying to get therapies directly into the organelle to counteract this decline for decades," says Abadir. "This is another attempt at delivering compounds using the body's natural systems, which may greatly reduce negative side effects both short and long term."
© Image - Phillip et al., PNAS Nexus, September 2022
This year's meeting will introduce you to the latest discoveries targeting mitochondria. Congress program.
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Mitochondria Targeted Near-Infrared Aggregation-Induced Emission for Photodynamic Ablation of Liver Cancer Cells
Multifunctional nano-photosensitizer was used for mitochondrial-targeting photodynamic ablation of liver cancer cells.
News Release, World Mitochondria Society, Berlin - Germany – September 6, 2022
The aggregation-induced emission photosensitizers (AIE-PSs) manifest a multitude of notable superiorities in terms of high specificity to organelles, high-efficient singlet oxygen (1O2) generation as well as enhanced fluorescence intensity, which provides a feasible approach to overcome the problems such as the insufficient generation of reactive oxygen species (ROS) caused by grave aggregation-induced quenching (ACQ) and the lack of specific targeting existing in traditional PSs, but extremely challenging.
Herein, a series of near-infrared (NIR) AIE luminogens (AIEgens) for targeting mitochondrial was devised and synthesized by regulating the D-A intensity assembly molecular engineering, which fabricating a progressively stronger intermolecular charge transfer (ICT) state to accelerate highly effective intersystem crossing (ISC) of excited electrons by the synergistic effect of thiophene and quinolinium.
- The optimal NIR AIE-PS (DTTVQ-OH) revealed excellent photostability, biocompatibility, precise mitochondria targeting, extremely high generation yield of 1O2 and superior phototoxicity in living HepG2 cells.
- Apoptosis assay and cell migration experiment further demonstrated that DTTVQ-OH could efficaciously restrain cell proliferation and induce/speed up cancer cell death.
- DTTVQ-OH could selectively distinguish cancer cells and normal cells by difference of fluorescence intensity in high resolution without the assist of any extra targeting ligands.
As a consequence, this work provides a rational and practicable strategy for the specific targeted molecular engineering of AIE-PSs, which gives impetus to the development of fluorescence imaging-guided photodynamic therapy fields.
© Image -Xue et al., Sensors and Actuators B: Chemical 2022
Targeting Mitochondria 2022 will dedicate a whole session to "Translational Therapies - Focus on Infrared Therapies". Submit a related abstract.
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Transplantation of Astrocytic Mitochondria for Intracerebral Hemorrhage Treatment
Level of Mn-SOD in neurons 21 days after hemmorage in mice that received mitochondria with and without Mn-SOD at one hour, seven days, and 14 days post-hemmorage. White arrows indicate the cells showing high Mn-SOD (red) in the neurons as a result of the treatment.
News Release, World Mitochondria Society, Berlin - Germany – August 17, 2022
Astrocytes release functional mitochondria that play regulatory and pro-survival functions upon entering adjacent cells. These released mitochondria can enter microglia and promote their reparative/pro-phagocytic phenotype that assists in hematoma cleanup and neurological recovery after intracerebral hemorrhage.
The robust increase in superoxide generation and elevated oxidative damage during intracerebral hemorrhage coincides with loss of the mitochondrial enzyme manganese superoxide dismutase (Mn-SOD). Tahiro et al. showed that intravenous transplantation of astrocytic mitochondria reversed the damaging effect of intracerebral hemorrhage.
When the astrocytic mitochondria entered the brain (and neurons) they restored Mn-SOD levels and reduced neurological deficits in male mice subjected to intracerebral hemorrhage. Astrocytic mitochondria prevented reactive oxygen species-induced oxidative stress and neuronal death by restoring neuronal Mn-SOD levels, while at the same time promoted neurite extension and upregulation of synaptogenesis-related gene expression. The mitochondria genome-encoded small peptide humanin could simulate mitochondria-transfer effect on neuronal Mn-SOD expression, oxidative stress, and neuroplasticity under intracerebral hemorrhage-like injury.
In summary, adoptive astrocytic mitochondrial transfer enhances neuronal Mn-SOD-mediated anti-oxidative defense and neuroplasticity in the brain, which potentiate functional recovery following intracerebral hemorrhage.
© Image -Tashiro et al., JNeurosci 2022
Targeting Mitochondria 2022 will dedicate a whole session for Mitochondrial transplantation and transfer. Conference Program.
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Selective Packaging of Mitochondrial Proteins into Extracellular Vesicles Prevents the Release of Mitochondrial DAMPs
Vesicles containing selective mitochondrial cargo are found in proximity to the plasma membrane (≤1 µm) but away from the main mitochondrial network (>1 µm)
News Release, World Mitochondria Society, Berlin - Germany – September 2, 2022
Most cells constitutively secrete mitochondrial DNA and proteins in extracellular vesicles. While EVs are small vesicles that transfer material between cells, Mitochondria-Derived Vesicles (MDVs) carry material specifically between mitochondria and other organelles. Mitochondrial content can enhance inflammation under pro-inflammatory conditions, though its role in the absence of inflammation remains elusive.
- Germain et al. demonstrated that cells actively prevent the packaging of pro-inflammatory, oxidized mitochondrial proteins that would act as damage-associated molecular patterns (DAMPs) into EVs.
- They found that the distinction between material to be included into EVs and damaged mitochondrial content to be excluded is dependent on selective targeting to one of two distinct MDV pathways.
- They showed that Optic Atrophy 1 (OPA1) and sorting nexin 9 (Snx9)-dependent MDVs are required to target mitochondrial proteins to EVs, while the Parkinson’s disease-related protein Parkin blocks this process by directing damaged mitochondrial content to lysosomes.
These results provide insight into the interplay between mitochondrial quality control mechanisms and mitochondria-driven immune responses.
© Image -Todkar et al., Nature Communications 2022
Dr. Marc Germain will join Targeting Mitochondria 2022 to extensively discuss those result in a session entitled "Extracellular Vesicles & Mitochondria: The Target". Conference Program.
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Researchers prove the potential of mitochondria-targeted chemotherapies
Schematic of oxygen-dependent regulation of mitochondrial transcription factor TFAM by pVHL, independent of the canonical substrate HIFα. mtDNA, mitochondrial DNA
News Release, World Mitochondria Society, Berlin - Germany – July 6, 2022
Researchers at Karolinska Institutet in Sweden have linked resistance to treatment for a deadly form of kidney cancer to low mitochondrial content in the cell. When the researchers increased the mitochondrial content with an inhibitor, the cancer cells responded to the treatment. Their findings, which are published in Nature Metabolism, offer hope for more targeted cancer drugs.
Mitochondria produce energy for the cell and require oxygen to do so. As such, they are the most oxygen-demanding component of the cell. But how mitochondria adapt in a low-oxygen environment and are linked to cancer therapy resistance has remained unknown.
“We’ve shown for the first time how the formation of new mitochondria is regulated in cells that lack oxygen and how this process is altered in cancer cells with VHL mutations,” says Associate Professor Susanne Schlisio, group leader at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet.
Healthy cells are prevented from becoming cancerous by a gene called von Hippel-Lindau (VHL). The 2019 Nobel Prize in Physiology or Medicine was awarded to the discovery that VHL was part of the cell’s oxygen detection system. Normally, VHL breaks down another protein called HIF. Consequently, when VHL is mutated, HIF accumulates and causes a disease called VHL syndrome in which the cells react as if they lack oxygen despite oxygen being present. VHL syndrome greatly increases the risk of tumours, both benign and malignant. VHL syndrome-induced kidney cancer has a poor prognosis, with a five-year survival rate of barely 12 per cent.
In the present study, the researchers examined the protein content of cancer cells from patients with different variants of VHL syndrome, and how they differed from another group of individuals with a special VHL mutation called Chuvash, a mutation involved in hypoxia-sensing disorders without any tumor development. Those with the Chuvash VHL-mutation had normal mitochondria in their cells, while those with VHL syndrome mutation had few.
To increase the amount of mitochondrial content in VHL related kidney cancer cells, the researchers treated these tumours with an inhibitor of a mitochondrial protease called “LONP1”. The cells then became susceptible to the cancer drug sorafenib, which they had previously resisted. In mouse studies, this combination treatment led to reduced tumour growth.
“We hope that this new knowledge will pave the way for more specific LONP1 protease inhibitors to treat VHL-related clear cell kidney cancer,” says the study’s first author Shuijie Li, postdoctoral researcher in the Schlisio’s group. “Our finding can be linked to all VHL syndromic cancers, such as the neuroendocrine tumours pheochromocytoma and paraganglioma, and not just kidney cancer.”
Targeting Mitochondria 2022 will cover all recent advances in the implication of mitohcondria in chronic diseases, as well as in the acceleration of mitochondrial medicine. If you are currently working on these topics, you can submit your abstract.
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Targeting Mitochondria 2022 Congress
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