Autophagy is a process by which cytoplasmic organelles can be catabolized either to remove defective structures or as a means of providing macromolecules for energy generation under conditions of nutrient starvation. In this study we demonstrate that mitochondrial autophagy is induced by hypoxia, that this process requires the hypoxia-dependent factor-1-dependent expression of BNIP3 and the constitutive expression of Beclin-1 and Atg5, and that in cells subjected to prolonged hypoxia, mitochondrial autophagy is an adaptive metabolic response which is necessary to prevent increased levels of reactive oxygen species and cell death.The survival of metazoan organisms is dependent upon their ability to efficiently generate energy through the process of mitochondrial oxidative phosphorylation in which reducing equivalents, derived from the oxidation of acetyl CoA in the tricarboxylic acid cycle, are transferred from NADH and FADH 2 to the electron transport chain and ultimately to O 2 , a process which produces an electrochemical gradient that is used to synthesize ATP (1). Although oxidative phosphorylation is more efficient than glycolysis in generating ATP, it carries the inherent risk of generating reactive oxygen species (ROS) 2 as a result of electrons prematurely reacting with O 2 at respiratory complex I or complex III. Transient, low level ROS production is utilized for signal transduction in metazoan cells, but prolonged elevations of ROS result in the oxidation of protein, lipid, and nucleic acid leading to cell dysfunction or death.O 2 delivery and utilization must, therefore, be precisely regulated to maintain energy and redox homeostasis.Hypoxia-inducible factor 1 (HIF-1) plays a key role in the regulation of oxygen homeostasis (2, 3). HIF-1 is a heterodimer composed of a constitutively expressed HIF-1␤ subunit and an O 2 -regulated HIF-1␣ subunit (4). Under aerobic conditions, HIF-1␣ is hydroxylated on proline residue 402 and/or 564 by prolyl hydroxylase 2 a dioxygenase that utilizes O 2 and ␣-ketoglutarate as co-substrates with ascorbate as co-factor in a reaction that generates succinate and CO 2 as side products (5-8). Under hypoxic conditions the rate of hydroxylation declines, either as a result of inadequate substrate (O 2 ) or as a result of hypoxia-induced mitochondrial ROS production, which may oxidize Fe(II) in the catalytic center of the hydroxylase (9, 10). Hydroxylated HIF-1␣ is bound by the von HippelLindau protein, which recruits a ubiquitin protein ligase complex that targets HIF-1␣ for proteasomal degradation (11)(12)(13)(14).HIF-1 regulates the transcription of hundreds of genes in response to hypoxia (15, 16), including the EPO (17) and VEGF (18) genes that encode proteins required for erythropoiesis and angiogenesis, respectively, which serve to increase O 2 delivery. In addition, HIF-1 controls a series of molecular mechanisms designed to maintain energy and redox homeostasis. First, HIF-1 coordinates a switch in the composition of cytochrome c oxidase (mitochondrial electron-transp...

Abstract-Ischemia is a stimulus for production of angiogenic cytokines that activate local vascular cells and mobilize angiogenic cells to the circulation. These responses are impaired in elderly patients with peripheral arterial disease. Hypoxia-inducible factor (HIF)-1 mediates adaptive responses to ischemia, including production of angiogenic cytokines. In this study, we demonstrate that aging and HIF-1 loss-of-function impair the expression of multiple angiogenic cytokines, mobilization of angiogenic cells, maintenance of tissue viability, and recovery of limb perfusion following femoral artery ligation. We show that HIF-1 directly activates transcription of the gene encoding stem cell factor and that mice lacking the cognate receptor C-KIT have impaired recovery from ischemia. Administration of AdCA5, an adenovirus encoding a constitutively active form of HIF-1␣, improved the recovery of perfusion in older mice to levels similar to those in young mice. Injection of AdCA5 into nonischemic limb was sufficient to increase the number of circulating angiogenic cells. These results indicate that HIF-1 activity is necessary and sufficient for the mobilization of angiogenic cells and that HIF-1␣ gene therapy can counteract the pathological effects of aging in a mouse model of limb ischemia.

Inebilizumab had an acceptable safety profile in relapsing MS patients and showed a trend in reductions in new/newly enlarging and gadolinium-enhancing lesions.

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in organs and tissues. If untreated, patients with the severe phenotype die within the first decade of life. Early diagnosis is crucial to prevent the development of fatal disease manifestations, prominently cardiac and respiratory disease, as well as cognitive impairment. However, the initial symptoms are nonspecific and impede early diagnosis. This review discusses common phenotypic manifestations in the order in which they develop. Similarities and differences in the three animal models for MPS I are highlighted. Earliest symptoms, which present during the first 6 months of life, include hernias, coarse facial features, recurrent rhinitis and/or upper airway obstructions in the absence of infection, and thoracolumbar kyphosis. During the next 6 months, loss of hearing, corneal clouding, and further musculoskeletal dysplasias develop. Finally, late manifestations including lower airway obstructions and cognitive decline emerge. Cardiac symptoms are common in MPS I and can develop in infancy. The underlying pathogenesis is in the intra- and extracellular accumulation of partially degraded GAGs and infiltration of cells with enlarged lysosomes causing tissue expansion and bone deformities. These interfere with the proper arrangement of collagen fibrils, disrupt nerve fibers, and cause devastating secondary pathophysiological cascades including inflammation, oxidative stress, and other disruptions to intracellular and extracellular homeostasis. A greater understanding of the natural history of MPS I will allow early diagnosis and timely management of the disease facilitating better treatment outcomes.