Mitochondrial flashes: new insights into mitochondrial ROS signalling and beyond

Abstract

Respiratory mitochondria undergo stochastic, intermittent bursts of superoxide production accompanied by transient depolarization of the mitochondrial membrane potential and reversible opening of the membrane permeability transition pore. These discrete events were named 'superoxide flashes' for the reactive oxygen species (ROS) signal involved, and 'mitochondrial flashes' (mitoflashes) for the entirety of the multifaceted and intertwined mitochondrial processes. In contrast to the flashless basal ROS production of 'homeostatic ROS' for redox regulation, bursting ROS production during mitoflashes may provide 'signalling ROS' at the organelle level, fulfilling distinctly different cell functions. Mounting evidence indicates that mitoflash frequency is richly regulated over a broad range, and represents a novel, universal, and 'digital' readout of mitochondrial functional status and of the mitochondrial stress response. An emerging view is that mitoflashes participate in vital processes including metabolism, cell differentiation, the stress response and ageing. These recent advances shed new light on the role of mitochondrial functional dynamics in health and disease.

Figure 1. Mitoflash is a complex phenomenon comprising multifaceted and intertwined processes

A cpYFP flash is associated with a transient loss of mitochondrial membrane potential (indexed by tetramethyl rhodamine methyl ester (TMRM)) (A), mitoSOX signal (B), DCF signal (modified from Zhang et al. 2013) (C), transient depletion of NADH (D) and FADH₂ (reflected by FAD⁺ autofluorescence) (E), and an MPT (evidenced by irreversible loss of Rhod-2 analogue) (modified from Wang et al. 2012) (F). NADH autofluorescence was measured by 720 nm two-photon excitation. FAD⁺ autofluorescence was measured between 500 and 650 nm at 488 nm excitation. Scale bar: 10 s for x-axis and 0.2ΔF/F₀ for y-axis in A, D, E and F; 20 s for x-axis and 1 arbitrary unit for y-axis in B and C.

Figure 2. Mitoflashes represent a universal and conserved mitochondrial activity

Mitoflashes are found across species in different tissues, cells and experimental systems. Their unitary properties are highly comparable. MTS: mitochondrial targeting signal peptide of cytochrome c oxidase subunit IV (COX IV) (for transgenic mouse and zebrafish) or succinate dehydrogenase (ubiquinone) iron-sulfur subunit (SDHB-1) (for transgenic C. elegans).

Figure 3. Schematic view of possible signalling roles of mitoflashes

Mitoflashes serve as an early predictor when lifespan is altered by diverse genetic, environmental and stochastic factors in C. elegans, and participate in early developmental (proliferation) and pathophysiological stress responses (hyperosmotic and apoptotic stress). Note that, except for a few cases, little is known about the specific pathways involved in mitoflash signalling. Continuous lines, activation (→) or inhibition (―|); dashed arrows, simplified signal pathway.