Mitochondrial retrograde signaling through UCP1-mediated inhibition of the plant oxygen-sensing pathway.

Mitochondrial retrograde signaling is an important component of intracellular stress signaling in eukaryotes. UNCOUPLING PROTEIN (UCP)1 is an abundant plant inner-mitochondrial membrane protein with multiple functions including uncoupled respiration and amino-acid transport1,2 that influences broad abiotic stress responses. Although the mechanism(s) through which this retrograde function acts is unknown, overexpression of UCP1 activates expression of hypoxia (low oxygen)-associated nuclear genes.3,4 Here we show in Arabidopsis thaliana that UCP1 influences nuclear gene expression and physiological response by inhibiting the cytoplasmic PLANT CYSTEINE OXIDASE (PCO) branch of the PROTEOLYSIS (PRT)6 N-degron pathway, a major mechanism of oxygen and nitric oxide (NO) sensing.5 Overexpression of UCP1 (UCP1ox) resulted in the stabilization of an artificial PCO N-degron pathway substrate, and stability of this reporter protein was influenced by pharmacological interventions that control UCP1 activity. Hypoxia and salt-tolerant phenotypes observed in UCP1ox lines resembled those observed for the PRT6 N-recognin E3 ligase mutant prt6-1. Genetic analysis showed that UCP1 regulation of hypoxia responses required the activity of PCO N-degron pathway ETHYLENE RESPONSE FACTOR (ERF)VII substrates. Transcript expression analysis indicated that UCP1 regulation of hypoxia-related gene expression is a normal component of seedling development. Our results show that mitochondrial retrograde signaling represses the PCO N-degron pathway, enhancing substrate function, thus facilitating downstream stress responses. This work reveals a novel mechanism through which mitochondrial retrograde signaling influences nuclear response to hypoxia by inhibition of an ancient cytoplasmic pathway of eukaryotic oxygen sensing.

Oxygen sensing in crustaceans: functions and mechanisms.

Animals that live in changing environments need to adjust their metabolism to maintain body functions, and sensing these changing conditions is essential for mediating the short- and long-term physiological and behavioral responses that make these adjustments. Previous research on nematodes and insects facing changing oxygen levels has shown that these animals rapidly respond using atypical soluble guanylyl cyclases (sGCs) as oxygen sensors connected to downstream cGMP pathways, and they respond more slowly using hypoxia-inducible transcription factors (HIFs) that are further modulated by oxygen-sensing prolyl hydroxylases (PHs). Crustaceans are known to respond in different ways to hypoxia, but the mechanisms responsible for sensing oxygen levels are more poorly understood than in nematodes and insects. Our paper reviews the functions of and mechanisms underlying oxygen sensing in crustaceans. Furthermore, using the oxygen sensing abilities of nematodes and insects as guides in analyzing available crustacean transcriptomes, we identified orthologues of atypical sGCs, HIFs, and PHs in crustaceans, including in their chemosensory organs and neurons. These molecules include atypical sGCs activated by hypoxia (Gyc-88E/GCY-31 and Gyc-89D/GCY-33) but not those activated by hyperoxia (GCY-35, GCY-36), as well as orthologues of HIF-α, HIF-ß, and PH. We offer possible directions for future research on oxygen sensing by crustaceans.

Evolution and physiology of neural oxygen sensing.

Major evolutionary trends in animal physiology have been heavily influenced by atmospheric O2 levels. Amongst other important factors, the increase in atmospheric O2 which occurred in the Pre-Cambrian and the development of aerobic respiration beckoned the evolution of animal organ systems that were dedicated to the absorption and transportation of O2, e.g., the respiratory and cardiovascular systems of vertebrates. Global variations of O2 levels in post-Cambrian periods have also been correlated with evolutionary changes in animal physiology, especially cardiorespiratory function. Oxygen transportation systems are, in our view, ultimately controlled by the brain related mechanisms, which senses changes in O2 availability and regulates autonomic and respiratory responses that ensure the survival of the organism in the face of hypoxic challenges. In vertebrates, the major sensorial system for oxygen sensing and responding to hypoxia is the peripheral chemoreflex neuronal pathways, which includes the oxygen chemosensitive glomus cells and several brainstem regions involved in the autonomic regulation of the cardiovascular system and respiratory control. In this review we discuss the concept that regulating O2 homeostasis was one of the primordial roles of the nervous system. We also review the physiology of the peripheral chemoreflex, focusing on the integrative repercussions of chemoreflex activation and the evolutionary importance of this system, which is essential for the survival of complex organisms such as vertebrates. The contribution of hypoxia and peripheral chemoreflex for the development of diseases associated to the cardiovascular and respiratory systems is also discussed in an evolutionary context.