Kidney proximal tubules (PTs) contain a high density of mitochondria, which are required to generate ATP to power solute transport. Mitochondrial dysfunction is implicated in the pathogenesis of numerous kidney diseases. Damaged mitochondria are thought to produce excess reactive oxygen species (ROS), which can lead to oxidative stress and activation of cell death pathways. MitoQ is a mitochondrial targeted anti‐oxidant that has shown promise in preclinical models of renal diseases. However, recent studies in nonkidney cells have suggested that MitoQ might also have adverse effects. Here, using a live imaging approach, and both in vitro and ex vivo models, we show that MitoQ induces rapid swelling and depolarization of mitochondria in PT cells, but these effects were not observed with SS‐31, another targeted anti‐oxidant. MitoQ consists of a lipophilic cation (Tetraphenylphosphonium [TPP]) joined to an anti‐oxidant component (quinone) by a 10‐carbon alkyl chain, which is thought to insert into the inner mitochondrial membrane (IMM). We found that mitochondrial swelling and depolarization was also induced by dodecyltriphenylphosphomium (DTPP), which consists of TPP and the alkyl chain, but not by TPP alone. Surprisingly, MitoQ‐induced mitochondrial swelling occurred in the absence of a decrease in oxygen consumption rate. We also found that DTPP directly increased the permeability of artificial liposomes with a cardiolipin content similar to that of the IMM. In summary, MitoQ causes mitochondrial swelling and depolarization in PT cells by a mechanism unrelated to anti‐oxidant activity, most likely because of increased IMM permeability due to insertion of the alkyl chain.
The unique molecular architecture of lipidic cubic phases (LCPs) and their cubosome dispersions comprise a well-defined, curved bilayer that spans the entire three-dimensional (3-D) material space, encompassing a network of two periodic, curved, and nonintersecting 3-D aqueous channels. The ensuing large lipid/water interfacial area makes these biomaterials an interesting matrix for the lateral immobilization of organocatalysts to catalyze organic reactions in confined water. Herein, we report for the first time the design, synthesis, assembly, and characterization of catalytically active LCPs and cubosomes and demonstrate their applicability as self-assembled, biomimetic, and recyclable nanoreactor scaffolds. Small-angle X-ray scattering, cryo-transmission electron microscopy, and dynamic light scattering were applied for the characterization of the mesophases. These mesophases can be recycled and enable efficient catalytic activity as well as modulation of the diastereo- and enantioselectivity for the aldol reaction of several benzaldehyde derivatives and cyclohexanone in water.
The iron chelator Deferasirox (DFX) causes severe toxicity in patients for reasons that were previously unexplained. Here, using the kidney as a clinically relevant in vivo model for toxicity together with a broad range of experimental techniques, including live cell imaging and in vitro biophysical models, we show that DFX causes partial uncoupling and dramatic swelling of mitochondria, but without depolarization or opening of the mitochondrial permeability transition pore. This effect is explained by an increase in inner mitochondrial membrane (IMM) permeability to protons, but not small molecules. The movement of water into mitochondria is prevented by altering intracellular osmotic gradients. Other clinically used iron chelators do not produce mitochondrial swelling. Thus, DFX causes organ toxicity due to an off-target effect on the IMM, which has major adverse consequences for mitochondrial volume regulation.
Lipidic cubic phases
(LCPs) can reduce Pd2+ salts to
palladium nanoparticles (PdNPs) of ∼5 nm size in their confined
water channels under mild conditions. The resulting PdNP-containing
LCPs were used as nanoreactor scaffolds to catalyze Suzuki–Miyaura
cross-coupling reactions in the aqueous channels of the mesophase.
To turn on catalysis, PdNP-containing LCPs were activated by swelling
the aqueous channels of the lipidic framework, thereby enabling diffusion
of the water-soluble substrates to the catalysts. The mesophases play
a threefold role: they act as reducing agents for Pd2+,
as limiting templates for their growth, and as support. The system
was characterized and investigated by small-angle X-ray scattering
(SAXS), cryo-transmission electron microscopy, dynamic light scattering,
and nuclear magnetic resonance. Bulk LCPs and three dispersed palladium/lipid
hybrid nanoparticle types were applied in the catalysis. The latterliposomes,
hexosomes, and cubosomescan be obtained by design through
combination of lipids and additives. The Suzuki–Miyaura cross-coupling
of 5-iodo-2′-deoxyuridine and phenylboronic acid was used as
a model reaction to study these systems. Bulk Pd-LCPs deliver the
Suzuki–Miyaura product in 24 h in conversions up to 98% at
room temperature, whereas with palladium/lipid dispersions at 40 °C,
68% of the starting material was transformed to the product after
72 h.
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