Redox Nanodomains Are Induced by and Control Calcium Signaling at the ER-Mitochondrial Interface

Abstract

The ER-mitochondrial interface is central to calcium signaling, organellar dynamics and lipid biosynthesis. The ER and mitochondrial membranes also host sources and targets of reactive oxygen species (ROS) but their local dynamics and relevance remained elusive since measurement and perturbation of ROS at the organellar interface has proven difficult. Employing drug-inducible synthetic ER-mitochondrial linkers, we overcame this problem and demonstrate that the ER-mitochondrial interface hosts a nanodomain of H2O2, which is induced by cytoplasmic [Ca2+] spikes and exert a positive feedback on calcium oscillations. H2O2 nanodomains originate from the mitochondrial cristae, which are compressed upon calcium signal propagation to the mitochondria, likely due to Ca2+-induced K+ and concomitant water influx to the matrix. Thus, ER-mitochondrial H2O2 nanodomains represent a novel component of inter-organelle communication, regulating calcium signaling and mitochondrial activities.

Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress

“…The H 2 O 2 nanodomains mentioned above [56] support the emerging concept that Ca 2+ signaling and the luminal redox state of the endoplasmic reticulum are intertwined, especially at the mitochondria-associated membranes (MAM) [114], [115]. Associated pH transients are accessible as well [29].…”

“…Interestingly, even within subcellular organelles, there are H 2 O 2 gradients·H 2 O 2 in the mitochondrial cristae space originates largely from mitochondrial Complex III, whereas mitochondrial Complexes I and II contribute to mitochondrial matrix H 2 O 2 [55]. In the cristae subspace “redox nanodomains” have been described, which are induced by and control calcium signaling at the ER-mitochondrial interface [56]·H 2 O 2 transients sensitize calcium ion release to maintain calcium oscillations [56].…”

An energetic view of stress: Focus on mitochondria

“…Pregnanolone is then exported to an adjacent organelle, the endoplasmic reticulum (ER), where a series of enzymatic reactions convert it to deoxycorticosterone (mostly in rodents) or 11-deoxycortisol (mostly in humans). The ER is closely associated with mitochondria in a number of tissues, where inter-organelle contacts are important for the function of mitochondria (Klecker et al, 2014; Booth et al, 2016). The terminal reaction, catalyzed by the mitochondrial enzyme 11β-hydroxylase (11βH) then generates cortisol (human) or corticosterone (rodent) in the mitochondrial matrix.…”

Mitochondrial junctions with cellular organelles: Ca2+ signalling perspective

“…ER-mitochondrial junctions are also sites of localised H 2 O 2 nanodomains that were recently directly measured and reported by D. Booth and colleagues [12]. In this elegant study from the G. Hajnoczky laboratory, the authors targeted the H 2 O 2 sensor HyPer [5] to the inducible linkers between the ER and mitochondria, and observed Ca 2+ -dependent redox nanodomains in the junctions between the organelles [12].…”

“…In this elegant study from the G. Hajnoczky laboratory, the authors targeted the H 2 O 2 sensor HyPer [5] to the inducible linkers between the ER and mitochondria, and observed Ca 2+ -dependent redox nanodomains in the junctions between the organelles [12]. Interestingly, H 2 O 2 transients potentiated ER Ca 2+ release [12]. Redox regulation of IP3Rs is well documented (e.g.…”