Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing

Abstract

Mitochondria play an important role in sensing both acute and chronic hypoxia in the pulmonary vasculature, but their primary oxygen-sensing mechanism and contribution to stabilization of the hypoxia-inducible factor (HIF) remains elusive. Alteration of the mitochondrial electron flux and increased superoxide release from complex III has been proposed as an essential trigger for hypoxic pulmonary vasoconstriction (HPV). We used mice expressing a tunicate alternative oxidase, AOX, which maintains electron flux when respiratory complexes III and/or IV are inhibited. Respiratory restoration by AOX prevented acute HPV and hypoxic responses of pulmonary arterial smooth muscle cells (PASMC), acute hypoxia-induced redox changes of NADH and cytochrome c, and superoxide production. In contrast, AOX did not affect the development of chronic hypoxia-induced pulmonary hypertension and HIF-1α stabilization. These results indicate that distal inhibition of the mitochondrial electron transport chain in PASMC is an essential initial step for acute but not chronic oxygen sensing.

The tardigradeHypsibius exemplarisas an emerging model to study the mitochondrial alternative oxidase at animal organismal level

“…intestinalis AOX in mitochondria of fruit flies [23][24][25] and mice [28][29]. The same applies to the mouse MRC complex III deficiency [9,11]. .…”

“…Moreover, it is suggested that AOX can bypass blockade or deficiency of the MRC complexes III and IV by restoring electron flow upstream of the MRC complex III. Consequently, AOX is considered to be an important element of a therapeutic strategy against impairment of these complexes [1,3,[9][10][11][12].…”

The Tardigrade Hypsibius Exemplaris as an Emerging Model to Study the Mitochondrial Alternative Oxidase at Animal Organismal Level

“…So far two other animal models, both obtained due to heterologous expression of the tunicate C. intestinalis AOX in fruit ies and mice, have been used in research on AOX impact on animal physiology and the enzyme possible application in therapy of human mitochondrial diseases (e.g. [1,3,[9][10][11][12]. The data obtained for H. exemplaris could supplement the models due to the presence of native AOX as well as simplicity of the tardigrade culture and AOX research in intact specimens.…”

“…The possibility to provide a complete or substantial protection against a range of phenotypes induced by the MRC complex IV de ciency or inhibition was also observed after expression of C. intestinalis AOX in mitochondria of fruit ies [23][24][25] and mice [28][29]. The same applies to the mouse MRC complex III de ciency [9,11]. .…”

“…Moreover, it is suggested that AOX can bypass blockade or de ciency of the MRC complexes III and IV by restoring electron ow upstream of the MRC complex III. Consequently, AOX is considered to be an important element of a therapeutic strategy against impairment of these complexes [1,3,[9][10][11][12].…”