Mitochondria are the energy factories of the cell and also serve as a checkpoint regulating programmed cell death. Not surprisingly, dysfunctional mitochondria are implicated in a variety of diseases ranging from metabolic disorders to cancer. Treatment of these diseases through the delivery of targeted drugs, however, is impeded by the difficulty of penetrating the membranes that define this organelle. The properties of this barrier serve as a major obstacle to drug delivery and a lack of effective transporters has hindered the advancement of mitochondrial medicine. Recently, however, synthetic transporters that show promise for the mito-specific delivery of bioactive cargos have begun to emerge. This review summarizes the most exciting of these developments and discusses their applications.

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A class of mitochondria-penetrating peptides (MPPs) was studied in an effort to optimize their applications in the delivery of bioactive cargo to this therapeutically important organelle. The sequence requirements for mitochondrial entry were monitored, and it was discovered that while an alternating cationic/hydrophobic residue motif is not required, the inclusion of a stretch of adjacent cationic amino acids can impede access to the organelle. In addition, a variety of N- and C-terminal cargo were tested to determine if there are limitations to the lipophilicity, charge, or polarity of compounds that can be transported to mitochondria by MPPs. The results reported demonstrate that these peptide sequences are versatile transporters that will have a range of biological applications.

Shear detection and mechanotransduction by arterial endothelium requires junctional complexes containing PECAM‐1 and VE‐cadherin, as well as firm anchorage to the underlying basement membrane. While considerable information is available for junctional complexes in these processes, gained largely from in vitro studies, little is known about the contribution of the endothelial basement membrane. Using resistance artery explants, we show that the integral endothelial basement membrane component, laminin 511 (laminin α5), is central to shear detection and mechanotransduction and its elimination at this site results in ablation of dilation in response to increased shear stress. Loss of endothelial laminin 511 correlates with reduced cortical stiffness of arterial endothelium in vivo, smaller integrin β1‐positive/vinculin‐positive focal adhesions, and reduced junctional association of actin–myosin II. In vitro assays reveal that β1 integrin‐mediated interaction with laminin 511 results in high strengths of adhesion, which promotes p120 catenin association with VE‐cadherin, stabilizing it at cell junctions and increasing cell–cell adhesion strength. This highlights the importance of endothelial laminin 511 in shear response in the physiologically relevant context of resistance arteries.

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