Edited by Ruma BanerjeeMitochondria are multifaceted and indispensable organelles required for cell performance. Accordingly, dysfunction to mitochondria can result in cellular decline and possibly the onset of disease. Cells use a variety of means to recover mitochondria and restore homeostasis, including the activation of retrograde pathways such as the mitochondrial unfolded protein response (UPR mt ). In this Minireview, we will discuss how cells adapt to mitochondrial stress through UPR mt regulation. Furthermore, we will explore the current repertoire of biological functions that are associated with this essential stress-response pathway.Mitochondria are double membrane organelles commonly associated with the production of cellular energy via oxidative phosphorylation (OXPHOS).2 Mitochondria are also required for the metabolism of nucleotides, amino acids, and lipids and have an essential function in regulating apoptosis. Maintaining mitochondrial integrity is therefore a key aspect in ensuring cellular and organismal viability. Consequently, a decline in mitochondrial function is frequently associated with the development of numerous diseases (1).Mitochondria are dependent on a diverse compilation of proteins to carry out their vital functions. However, the mitochondrial proteome is faced with various challenges, most notably the partitioning of protein encoding genes between the mitochondrial and nuclear genomes. Remarkably, the human mitochondrial genome only encodes ϳ1% of the total mitochondrial proteome with the remaining proteins being encoded by nuclear genes (2). Sophisticated mechanisms have evolved to efficiently transfer nuclear-encoded mitochondrial proteins to their proper organelle destination following translation on cytosolic ribosomes. To accomplish this complex task, proteins are sorted to mitochondria via targeting sequences that form characteristic amphipathic helices composed of positively charged residues. Such mitochondrial targeting sequences (MTS) are recognized and translocated via the mitochondrial Tom-Tim complex to their respective sub-organelle compartment (3). Exquisite coordination of expression between the mitochondrial and nuclear genomes exists during mitochondrial biogenesis, as failure in genome coordination can disrupt the precise stoichiometry of these OXPHOS complexes resulting in orphan subunit accumulation and proteotoxicity (4). Further contributing to mitochondrial proteotoxicity is the possible damage to the mitochondrial genome from reactive oxygen species (ROS) produced by OXPHOS machinery as well as the ill effects of various environmental toxins. Mechanisms must therefore exist to ensure the protection of the mitochondrial proteome.Quality control of the mitochondrial proteome includes the functions of mitochondrial chaperones that assist in proper protein folding and proteases that promote clearance of misfolded proteins (5). Each sub-compartment of mitochondria houses its own quality control machinery to ensure protein homeostasis and organelle function. ...

A deficiency in airway nitric oxide (NO) could contribute to pulmonary vaso-occlusion in sickle cell disease (SCD). We measured the fractional expired concentration of NO (FE NO ) by chemiluminescence during a slow vital capacity maneuver against a positive pressure of 16 cm H 2 O at an expiratory flow rate of 50 mL/sec in 44 stable ambulatory adults with SCD and 30 healthy controls. A history of acute chest syndrome was present in 29 patients, and 22 complained of dyspnea. Mean ± SD FE NO was significantly reduced in the SCD group compared with controls (14.8 ± 8.4 vs. 24.9 ± 13.5 ppb, P < 0.001). SCD patients with dyspnea had lower FE NO than those without dyspnea (10.1 ± 5.7 vs. 19.6 ± 8 ppb, P < 0.001) and those with a history of ACS had lower values than those no episodes of ACS (13.0 ± 8.3 vs. 18.4 ± 7.6 ppb, P < 0.05). There was a weak correlation between FE NO and percent-predicted DLCO (r = 0.4, P = 0.02) among the SCD patients. We conclude that exhaled NO is reduced in adults with SCD, and this may play a role in the pathogenesis of acute chest syndrome and chronic sickle cell lung disease. Am.

The mitochondrial unfolded protein response (UPR mt) is a stress-activated pathway promoting mitochondrial recovery and defense against infection. In C. elegans, the UPR mt is activated during infection with the pathogen Pseudomonas aeruginosa-but only transiently. As this may reflect a pathogenic strategy to target a pathway required for host survival, we conducted a P. aeruginosa genetic screen to uncover mechanisms associated with this temporary activation. Here, we find that loss of the P. aeruginosa acyl-CoA dehydrogenase FadE2 prolongs UPR mt activity and extends host survival. FadE2 shows substrate preferences for the coenzyme A intermediates produced during the breakdown of the branchedchain amino acids valine and leucine. Our data suggests that during infection, FadE2 restricts the supply of these catabolites to the host hindering host energy metabolism in addition to the UPR mt. Thus, a metabolic pathway in P. aeruginosa contributes to pathogenesis during infection through manipulation of host energy status and mitochondrial stress signaling potential.

review, we will provide an overview of mitochondrial recovery programs including mitochondrial dynamics, the mitochondrial unfolded protein response (UPR mt ), and mitophagy. We will then discuss the various approaches used by bacterial pathogens to target mitochondria, which result in mitochondrial dysfunction. Lastly, we will discuss how cells leverage mitochondrial recovery programs beyond their role in organelle repair, to promote host defense against pathogen infection.

• Background Although low concentrations of inhaled nitric oxide may by therapeutic, both nitric oxide and its oxidation product nitrogen dioxide are potentially toxic. The threshold limits for time-weighted average concentrations of nitric oxide and nitrogen dioxide issued by the American Conference of Governmental Industrial Hygienists are 25 and 3 ppm, respectively. The concentrations of these gases in the breathing space of hospital personnel during administration of nitric oxide to adult patients have not been reported.• Methods Air was sampled from the breathing zone of intensive care unit nurses via collar-mounted tubes during the nurses’ routine duties attending patients who were receiving inhaled nitric oxide at 5 or 20 ppm. The exhaust ports of the mechanical ventilators were left open to the room. Nitric oxide and nitrogen dioxide were chemically assayed as nitrite from sorbent tubes by using spectrophotometry. Ambient nitric oxide levels were measured at sequential distances from the ventilator by using chemiluminescence.• Results The time-weighted average concentrations of inspired gas for nurses during inhaled nitric oxide treatment were 0.45 ppm or less for nitric oxide and less than 0.29 ppm for nitrogen dioxide. Nitric oxide levels at the ventilator during delivery at 20 ppm were 9.2 ppm, but dropped off markedly beyond 0.6 m (2 ft), to a mean of about 30 ppb.• Conclusion Inhaled nitric oxide therapy at doses up to 20 ppm does not appear to pose a risk of excessive occupational exposure to nitric oxide or nitrogen dioxide to nurses during routine delivery of critical care.