Early Exposure to General Anesthesia Disturbs Mitochondrial Fission and Fusion in the Developing Rat Brain

Abstract

Background General anesthetics induce apoptotic neurodegeneration in the developing mammalian brain. General anesthesia (GA) also causes significant disturbances in mitochondrial morphogenesis during intense synaptogenesis. Mitochondria are dynamic organelles that undergo remodeling via fusion and fission. The fine balance between these two opposing processes determines mitochondrial morphometric properties, allowing for their regeneration and enabling normal functioning. As mitochondria are exquisitely sensitive to anesthesia-induced damage, we examined how GA affects mitochondrial fusion/fission. Methods Seven-day-old rat pups received anesthesia containing a sedative dose of midazolam followed by a combined nitrous oxide and isoflurane anesthesia for 6 h. Results GA causes 30% upregulation of reactive oxygen species (n = 3–5 pups/group), accompanied by a 2-fold downregulation of an important scavenging enzyme, superoxide dismutase (n = 6 pups/group). Reactive oxygen species upregulation is associated with impaired mitochondrial fission/fusion balance, leading to excessive mitochondrial fission. The imbalance between fission and fusion is due to acute sequestration of the main fission protein, dynamin-related protein 1, from the cytoplasm to mitochondria, and its oligomerization on the outer mitochondrial membrane. These are necessary steps in the formation of the ring-like structures that are required for mitochondrial fission. The fission is further promoted by GA-induced 40% downregulation of cytosolic mitofusin-2, a protein necessary for maintaining the opposing process, mitochondrial fusion (n = 6 pups/group). Conclusions Early exposure to GA causes acute reactive oxygen species upregulation and disturbs the fine balance between mitochondrial fission and fusion, leading to excessive fission and disturbed mitochondrial morphogenesis. These effects may play a causal role in GA-induced developmental neuroapoptosis.

Carbon monoxide modulates cytochrome oxidase activity and oxidative stress in the developing murine brain during isoflurane exposure

“…However, the underlying mechanisms of free radical production caused by anesthetics are not well understood. Consistent with prior work, we demonstrate that 1-hour exposure to isoflurane causes lipid peroxidation and increases CcOX activity in the forebrain of 7 day old male mice (9, 10, 34, 36). CO, unlike isoflurane, has the potential to either cause or limit ROS production depending on the mitochondrial transmembrane potential, and stimulates or reversibly inhibits CcOX depending on the concentration of exposure (18–21).…”

“…Isoflurane and a variety of commonly used anesthetic agents have been shown to induce ROS and reactive nitrogen species within developing neurons (9, 10, 34). However, depending on the resultant transmembrane potential and electron flux, CO has the potential to either cause deleterious free radical production within mitochondria or, alternatively, can exert cytoprotective properties by limiting oxidative stress (21).…”

“…Oxidative stress is an important mediator of anesthesia-induced neurotoxicity in the developing brain (10). However, the underlying mechanisms of free radical production caused by anesthetics are not well understood.…”

Altered Mitochondrial Dynamics Contributes to Propofol-induced Cell Death in Human Stem Cell–derived Neurons

“…Previous studies have shown that exposure of neonatal rat pups to general anesthetics induces significant increases in mitochondrial fission. 25, 26 However, the role of mitochondrial dynamics and related pathways in propofol-induced neurotoxicity has yet to be investigated.…”

Molecular pathways of mitochondrial dysfunctions: Possible cause of cell death in anesthesia-induced developmental neurotoxicity

“…In particular, compelling evidence has shown that GA (9 mg/kg midazolam + 75% nitrous oxide + 0.75% isoflurane) significantly decreases expression of Mfn-2, while increases the expression of DLP1, which impair mitochondrial fission/fusion balance, leading to excessive mitochondrial fission. The authors also showed that this disequilibrium maybe result from excessive ROS production (Boscolo et al, 2013). Consistent with this result, another group showed similar findings that Ketamine also enhanced mitochondrial fission as well as ROS production in human neural stem cells (Bai et al, 2013).…”