Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression

Abstract

Mitochondria are organelles with a highly dynamic ultrastructure maintained by a delicate equilibrium between its fission and fusion rates. Understanding the factors influencing this balance is important as perturbations to mitochondrial dynamics can result in pathological states. As a terminal site of nutrient oxidation for the cell, mitochondrial powerhouses harness energy in the form of ATP in a process driven by the electron transport chain. Contemporaneously, electrons translocated within the electron transport chain undergo spontaneous side reactions with oxygen, giving rise to superoxide and a variety of other downstream reactive oxygen species (ROS). Mitochondrially-derived ROS can mediate redox signaling or, in excess, cause cell injury and even cell death. Recent evidence suggests that mitochondrial ultrastructure is tightly coupled to ROS generation depending on the physiological status of the cell. Yet, the mechanism by which changes in mitochondrial shape modulate mitochondrial function and redox homeostasis is less clear. Aberrant mitochondrial morphology may lead to enhanced ROS formation, which, in turn, may deteriorate mitochondrial health and further exacerbate oxidative stress in a self-perpetuating vicious cycle. Here, we review the latest findings on the intricate relationship between mitochondrial dynamics and ROS production, focusing mainly on its role in malignant disease.

Keywords: cancer; mitochondrial dynamics; mitochondrial ultrastructure; oxidative stress; reactive oxygen species; redox signaling; superoxide.

Figure 1

Changing cell fates depending on oxidative damage extent and mitochondrial dynamics. Under mild oxidative stress conditions (top), clearance of defective mitochondrion (yellow) by mitophagy reduces ROS levels and enhances cell survival. Acute oxidative stress (bottom) promotes extensive mitochondrial fission and dysfunction that ultimately leads to elevated ROS, loss of mitochondrial integrity (green) and apoptotic cell death.

Figure 2

Simplified relationship between ROS-induced redox signaling and mitochondrial dynamics. ROS stimuli are recognized by redox sensors (top), which transduce the signal to their respective effector kinases (center). Phosphorylation by these kinases can either inhibit mitochondrial fusion (red) or stimulate fission (green) proteins that results in the shift of the overall balance from elongated to fragmented morphology (bottom). As indicated, Ras/ERK MAPK signaling involves multiple kinases. Redox sensor for mammalian cyclin C pathway has not yet been determined.

Figure 3

Drivers of fission-induced mitochondrial ROS production. Mitochondrial network fragmentation can occur at both extremes of ∆Ψ_m. Whereas low ∆Ψ_m values result from insults causing mitochondrial dysfunction (top), high ∆Ψ_m values can be achieved by metabolic stimulation such as with high glucose (bottom). Both stimuli result in fragmented organelles and subsequent generation of superoxide by ETC.

Figure 4

The vicious cycle of mitochondrial fragmentation and ROS production. Fission of the mitochondrial network, such as during oxidative stress (Figure 2), induces mitochondrial ROS generation (Figure 3) initiating a self-perpetuating cycle promoting mitochondrial dysfunction, cell cycle progression and genetic mutation that stimulates neoplastic growth and tumor initiation.