Mitochondrial Flash: Integrative Reactive Oxygen Species and pH Signals in Cell and Organelle Biology

Abstract

Significance: Recent breakthroughs in mitochondrial research have advanced, reshaped, and revolutionized our view of the role of mitochondria in health and disease. These discoveries include the development of novel tools to probe mitochondrial biology, the molecular identification of mitochondrial functional proteins, and the emergence of new concepts and mechanisms in mitochondrial function regulation. The discovery of “mitochondrial flash” activity has provided unique insights not only into real-time visualization of individual mitochondrial redox and pH dynamics in live cells but has also advanced understanding of the excitability, autonomy, and integration of mitochondrial function in vivo. Recent Advances: The mitochondrial flash is a transient and stochastic event confined within an individual mitochondrion and is observed in a wide range of organisms from plants to Caenorhabditis elegans to mammals. As flash events involve multiple transient concurrent changes within the mitochondrion (e.g., superoxide, pH, and membrane potential), a number of different mitochondrial targeted fluorescent indicators can detect flash activity. Accumulating evidence indicates that flash events reflect integrated snapshots of an intermittent mitochondrial process arising from mitochondrial respiration chain activity associated with the transient opening of the mitochondrial permeability transition pore. Critical Issues: We review the history of flash discovery, summarize current understanding of flash biology, highlight controversies regarding the relative roles of superoxide and pH signals during a flash event, and bring forth the integration of both signals in flash genesis. Future Directions: Investigations using flash as a biomarker and establishing its role in cell signaling pathway will move the field forward. Antioxid. Redox Signal. 25, 534–549.

Mitochondria, Bioenergetics and Apoptosis in Cancer

“…Are pH and ROS flicker 63 related to membrane potential flicker? Recent work has shown that, in addition to membrane potential flicker (measured via TMRE), pH may also flicker and the mitochondria release “pufs” or ROS.…”

Mitochondrial flashes: From indicator characterization to in vivo imaging

“…In addition, physiological and pathological perturbations, such as metabolic substrates [16, 20], electrical stimulation [17, 21], Ca 2+ [28, 49], ischemic-reperfusion [10, 43], insulin resistance [18], and mitochondrial stresses [20, 48], also modulate mitochondrial flash frequency. Taken together, increasing evidence suggests that mitochondrial flash is a composite biomarker that integrates mitochondrial functions including respiration, ROS production, pH regulation and mPTP opening [50]. Thus, monitoring this single mitochondrial event is a useful tool for studying the role of individual mitochondria in cell signaling, function and dysfunction [50].…”

“…Taken together, increasing evidence suggests that mitochondrial flash is a composite biomarker that integrates mitochondrial functions including respiration, ROS production, pH regulation and mPTP opening [50]. Thus, monitoring this single mitochondrial event is a useful tool for studying the role of individual mitochondria in cell signaling, function and dysfunction [50]. …”

“…Eight years after the first report on cpYFP as a superoxide indicator and the detection of single mitochondrial superoxide flashes [10], many exciting advances have been made and the significance of this single mitochondrial event in cell physiology and pathology has been gradually recognized [50–52]. In more than 40 publications, mitochondrial flash events have been detected in various biological systems ranging from plants, C. elegans , and zebrafish to rodents and human cells [50]. More importantly, when the mechanisms underlying mitochondrial flash generation unfolds, it provides the field with a new view on how mitochondrion actively integrates its functions, including metabolism, ROS, pH, and mPTP.…”

“…We have shown that muscle contraction induced mitochondrial flashes, which provided ROS to further support contractility [17, 21]. Extensive discussion over the pathophysiological significance of mitochondrial flash can be found in a recent review paper [50]. …”