Mitochondria are fundamental for metabolic homeostasis in all multicellular eukaryotes. In the nervous system, mitochondria-generated adenosine triphosphate (ATP) is required to establish appropriate electrochemical gradients and reliable synaptic transmission. Notably, several mitochondrial defects have been identified in central nervous system disorders. Membrane leakage and electrolyte imbalances, pro-apoptotic pathway activation, and mitophagy are among the mechanisms implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s disease, as well as ischemic stroke. In this review, we summarize mitochondrial pathways that contribute to disease progression. Further, we discuss pathological states that damaged mitochondria impose on normal nervous system processes and explore new therapeutic approaches to mitochondrial diseases.

Difluoroboron β–diketonate poly(lactic acid) materials exhibit both fluorescence (F) and oxygen sensitive room-temperature phosphorescence (RTP). Introduction of halide heavy atoms (Br and I) is an effective strategy to control the oxygen sensitivity in these materials. A series of naphthyl-phenyl (nbm) dye derivatives with hydrogen, bromide and iodide substituents were prepared for comparison. As nanoparticles, the hydrogen derivative was hypersensitive to oxygen (0–0.3%), while the bromide analogue was suited for hypoxia detection (0–3% O2). The iodo derivative, BF2nbm(I)PLA, showed excellent F to RTP peak separation and an 0–100% oxygen sensitivity range unprecedented for metal-free RTP emitting materials. Due to the dual emission and unconventionally long RTP lifetimes of these O2 sensing materials, a portable, cost-effective camera was used to quantify oxygen levels via lifetime and red/green/blue (RGB) ratiometry. The hypersensitive H dye was well matched to lifetime detection, simultaneous lifetime and ratiometric imaging was possible for the bromide analogue, whereas the iodide material, with intense RTP emission and a shorter lifetime, was suited for RGB ratiometry. To demonstrate the prospects of this camera/material design combination for bioimaging, iodide boron dye-PLA nanoparticles were applied to a murine wound model to detect oxygen levels. Surprisingly, wound oxygen imaging was achieved without covering (i.e. without isolating from ambient conditions, air). Additionally, would healing was monitored via wound size reduction and associated oxygen recovery, from hypoxic to normoxic. These single-component materials provide a simple tunable platform for biological oxygen sensing that can be deployed to spatially resolve oxygen in a variety of environments.

Treatment of many pathologies of the brain could be improved markedly by the development of noninvasive therapeutic approaches that elicit robust, endothelial cell-selective gene expression in specific brain regions that are targeted under MR image guidance. While focused ultrasound (FUS) in conjunction with gasfilled microbubbles (MBs) has emerged as a noninvasive modality for MR image-guided gene delivery to the brain, it has been used exclusively to transiently disrupt the blood-brain barrier (BBB), which may induce a sterile inflammation response. Here, we introduce an MR image-guided FUS method that elicits endothelialselective transfection of the cerebral vasculature (i.e., "sonoselective" transfection), without opening the BBB. We first determined that activating circulating, cationic plasmid-bearing MBs with pulsed low-pressure (0.1 MPa) 1.1-MHz FUS facilitates sonoselective gene delivery to the endothelium without MRI-detectable disruption of the BBB. The degree of endothelial selectivity varied inversely with the FUS pressure, with higher pressures (i.e., 0.3-MPa and 0.4-MPa FUS) consistently inducing BBB opening and extravascular transfection. Bulk RNA sequencing analyses revealed that the sonoselective low-pressure regimen does not up-regulate inflammatory or immune responses. Single-cell RNA sequencing indicated that the transcriptome of sonoselectively transfected brain endothelium was unaffected by the treatment. The approach developed here permits targeted gene delivery to blood vessels and could be used to promote angiogenesis, release endothelial cellsecreted factors to stimulate nerve regrowth, or recruit neural stem cells.focused ultrasound | microbubbles | endothelium | gene delivery

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BackgroundArteriogenesis is initiated by increased shear stress and is thought to continue until shear stress is returned to its original “set point.” However, the molecular mechanism(s) through which shear stress set point is established by endothelial cells (ECs) are largely unstudied. Here, we tested the hypothesis that DNA methyltransferase 1 (DNMT1)–dependent EC DNA methylation affects arteriogenic capacity via adjustments to shear stress set point.Methods and ResultsIn femoral artery ligation–operated C57BL/6 mice, collateral artery segments exposed to increased shear stress without a change in flow direction (ie, nonreversed flow) exhibited global DNA hypermethylation (increased 5‐methylcytosine staining intensity) and constrained arteriogenesis (30% less diameter growth) when compared with segments exposed to both an increase in shear stress and reversed‐flow direction. In vitro, ECs exposed to a flow waveform biomimetic of nonreversed collateral segments in vivo exhibited a 40% increase in DNMT1 expression, genome‐wide hypermethylation of gene promoters, and a DNMT1‐dependent 60% reduction in proarteriogenic monocyte adhesion compared with ECs exposed to a biomimetic reversed‐flow waveform. These results led us to test whether DNMT1 regulates arteriogenic capacity in vivo. In femoral artery ligation–operated mice, DNMT1 inhibition rescued arteriogenic capacity and returned shear stress back to its original set point in nonreversed collateral segments.ConclusionsIncreased shear stress without a change in flow direction initiates arteriogenic growth; however, it also elicits DNMT1‐dependent EC DNA hypermethylation. In turn, this diminishes mechanosensing, augments shear stress set point, and constrains the ultimate arteriogenic capacity of the vessel. This epigenetic effect could impact both endogenous collateralization and treatment of arterial occlusive diseases.