Aims: Determine the mechanism by which C-terminus of HSC70-interacting protein (CHIP) induction alters neuronal survival under conditions of mitochondrial stress induced by oxygen glucose deprivation. Results: We report that animals deficient in the E3 ubiquitin ligase, CHIP, have high baseline levels of central nervous system protein oxidation and lipid peroxidation, reduced antioxidant defenses, and decreased energetic status. Stress-associated molecules typically linked to Parkinson's disease such as the mitochondrial kinase, PTENinducible putative kinase 1 (PINK1), and another E3 ligase, Parkin, are upregulated in brains from CHIP knockout (KO) animals. Utilizing a novel biotin-avidin capture technique, we found that the oxidation status of Parkin and the mitochondrial fission protein, dynamin-related protein 1 (Drp1), are altered in a CHIP-dependent manner. We also found that following oxygen-glucose deprivation (OGD), the expression of CHIP, PINK1, and the autophagic marker, LC3, increase and there is activation of the redox-sensitive kinase p66shc . Under conditions of OGD, CHIP relocalizes from the cytosol to mitochondria. Mitochondria from CHIP KO mice have profound impairments in stress response induced by calcium overload, resulting in accelerated permeability transition activity. While CHIP-deficient neurons are morphologically intact, they are more susceptible to OGD consistent with a previously unknown neuroprotective role for CHIP in maintaining mitochondrial homeostasis. Innovation: CHIP relocalization to the mitochondria is essential for the regulation of mitochondrial integrity and neuronal survival following OGD. Conclusions: CHIP is an essential regulator of neuronal bioenergetics and redox tone. Altering the expression of this protein has profound effects on neuronal survival when cells are exposed to OGD. Antioxid. Redox Signal. 23, 535-549.

The isocitrate dehydrogenase (IDH) enzymes were initially identified as essential components of the Krebs cycle. IDH mutations were thought to be incompatible with cell survival. However, 90% of glioblastomas were recently shown to be associated with somatic mutations in these enzymes, indicating a possible role for IDH in promoting cellular survival in hypoxic environments. Our proteomic analysis of rats given 10 minutes of middle cerebral artery occlusion to induce transient ischemia demonstrates a significant decrease in IDH expression. We have recapitulated this decrease in an in vitro model using primary cortical neurons exposed to acute oxygen and glucose deprivation. Given the role of IDHs in energy metabolism and antioxidant production, we hypothesize that the IDHs may serve as first-line, rapid-response enzymes that regulate survival in environments of energetic or oxidative stress. In order to identify the specific events that regulate IDH enzymes, HT-22 neural cells were subjected to either a selective energetic challenge or a pure oxidative stress. In response to the non-lethal energetic challenge induced by substituting galactose for glucose, we observed increased IDH1, 2, and 3 expression and cessation of cellular proliferation. No change in expression of any IDH isoform was observed when neural cells were subjected to subtoxic oxidative stress via glutathione depletion. Taken together, these data imply that IDH expression rapidly responds to changes in energetic status, but not to oxidative stress. These data also suggest that IDH enzymes respond not only to allosteric modulation, but can also change patterns of expression in response to moderate stress in an effort to maximize ATP production and survival.

Introduction Transplant candidate participation in the Living Donor Navigator Program is associated with an increased likelihood of achieving living donor kidney transplantation; yet not every transplant candidate participates in navigator programming. Research Question We sought to assess interest and ability to participate in the Living Donor Navigator Program by the degree of social vulnerability. Design Eighty-two adult kidney-only candidates initiating evaluation at our center provided Likert-scaled responses to survey questions on interest and ability to participate in the Living Donor Navigator Program. Surveys were linked at the participant-level to the Centers for Disease Control and Prevention Social Vulnerability Index and county health rankings and overall social vulnerability and subthemes, individual barriers, telehealth capabilities/ knowledge, interest, and ability to participate were assessed utilizing nonparametric Wilcoxon ranks sums tests, chi-square, and Fisher's exact tests. Results Participants indicating distance as a barrier to participation in navigator programming lived approximately 82 miles farther from our center. Disinterested participants lived in areas with the highest social vulnerability, higher physical inactivity rates, lower college education rates, and higher uninsurance (lack of insurance) and unemployment rates. Similarly, participants without a computer, who never heard of telehealth, and who were not encouraged to participate in telehealth resided in areas of highest social vulnerability. Conclusion These data suggest geography combined with being from under-resourced areas with high social vulnerability was negatively associated with health care engagement. Geography and poverty may be surrogates for lower health literacy and fewer health care interactions.

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Cilia are microtubule-based organelles that can be motile or immotile (primary) and they are present on nearly every cell in the body. Their assembly requires a highly conserved process called intraflagellar transport (IFT) which mediates bidirectional movement of protein complexes between the base and tip of the cilium. Although once thought of as a vestigial organelle, the primary cilium is now known to have essential sensory and signaling roles. Disruption of this organelle in mice results in embryonic lethality and is associated with defects in left-right body axis specification, neural tube closure and patterning, and altered digit formation in the limb bud. In part this is due to aberrant coordination of Shh, Wnt, and PDGFR-α signaling which require the cilium for normal regulation. In addition, impaired ciliary function is thought to be a causative factor in numerous disease phenotypes in mice and humans, such as retinitis pigmentosa, hydrocephalus, and cystic lesions in the kidney, liver, and pancreas. One function of the primary cilia is thought to be that of mechanosensor that detects fluid movement through the lumen of tubules or ducts. To better analyze the function of cilia in the absence of the severe developmental defects and lethality, we utilized conditional alleles of two IFT genes to induce cilia loss systemically in adult mice or in specific tissues. As expected, disruption of cilia throughout the body or in the kidney during late gestation or in the perinatal period resulted in a rapid onset and severe cystic kidney phenotype and death around weaning age. In contrast when cilia loss was induced systemically in 8 to 12 week old mice a pronounced cystic kidney phenotype was not evident until nearly a year after cilia were ablated. This unexpected outcome indicates that loss of cilia mediated mechanosensation in itself is not sufficient to cause cyst development. Possible mechanisms behind the delayed cyst formation in the adult induced mutants will be discussed. While the cystic kidney phenotype was greatly attenuated in the adult-induced mutants, we did uncover an additional role for cilia in regulating energy homeostasis as the conditional mutants became obese. The increased weight gain was due to hyperphagia and not to changes in activity or metabolism. Further analyses demonstrate that the obesity phenotype can be recapitulated by the loss of cilia on CNS neurons and more specifically by loss of cilia on proopiomelanocortin (POMC) neurons in the hypothalamus. These data suggest that primary cilia function as a sensory organelle involved in reception, transmission, or regulation of satiety signals, possibly involving the insulin or leptin signaling axis.