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."

Source.

Article DOI.

© Image - Phillip et al., PNAS Nexus, September 2022

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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.

Paper DOI.

© Image -Todkar et al., Nature Communications 2022

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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.

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© Image -Xue et al., Sensors and Actuators B: Chemical 2022

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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.

Paper DOI.

© Image -Tashiro et al., JNeurosci 2022

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