Unraveling the role and mechanism of mitochondria in postoperative cognitive dysfunction: a narrative review

Abstract

Postoperative cognitive dysfunction (POCD) is a frequent neurological complication encountered during the perioperative period with unclear mechanisms and no effective treatments. Recent research into the pathogenesis of POCD has primarily focused on neuroinflammation, oxidative stress, changes in neural synaptic plasticity and neurotransmitter imbalances. Given the high-energy metabolism of neurons and their critical dependency on mitochondria, mitochondrial dysfunction directly affects neuronal function. Additionally, as the primary organelles generating reactive oxygen species, mitochondria are closely linked to the pathological processes of neuroinflammation. Surgery and anesthesia can induce mitochondrial dysfunction, increase mitochondrial oxidative stress, and disrupt mitochondrial quality-control mechanisms via various pathways, hence serving as key initiators of the POCD pathological process. We conducted a review on the role and potential mechanisms of mitochondria in postoperative cognitive dysfunction by consulting relevant literature from the PubMed and EMBASE databases spanning the past 25 years. Our findings indicate that surgery and anesthesia can inhibit mitochondrial respiration, thereby reducing ATP production, decreasing mitochondrial membrane potential, promoting mitochondrial fission, inducing mitochondrial calcium buffering abnormalities and iron accumulation, inhibiting mitophagy, and increasing mitochondrial oxidative stress. Mitochondrial dysfunction and damage can ultimately lead to impaired neuronal function, abnormal synaptic transmission, impaired synthesis and release of neurotransmitters, and even neuronal death, resulting in cognitive dysfunction. Targeted mitochondrial therapies have shown positive outcomes, holding promise as a novel treatment for POCD.

Keywords: Cognitive complication; Electron transport chain deficiency; Mitochondria; Mitochondrial dysfunction; Mitophagy; Neuroinflammation; Oxidative stress; Postoperative cognitive dysfunction.

Fig. 1

The impact of surgery and anesthesia on mitochondrial function. Surgery and anesthesia, especially general anesthesia, can have extensive effects on mitochondrial function during the perioperative period. Surgery and anesthesia can lead to increased levels of mitochondrial oxidative stress and further generation of ROS by promoting mitochondrial fission, forming a vicious cycle of oxidative stress. General anesthetic drugs can inhibit mitochondrial respiration and interfere with ATP production. Surgery and anesthesia can lead to mitochondrial calcium overload and iron homeostasis imbalance, and cause cell death (apoptosis and ferroptosis) through a series of downstream mechanisms. Surgery and anesthesia can affect mitochondrial biogenesis and dynamics (transport, fusion, fission), and interfere with important mitochondrial quality control mechanisms such as the unfolded protein response and mitophagy, leading to mitochondrial dysfunction. In addition, general anesthesia can also affect mitochondrial dynamics and mitochondrial function by increasing the phosphorylation of Tau protein

Fig. 2

The role and mechanism of mitochondrial calcium overload in POCD. Anesthesia and surgery increase the calcium influx into neurons by opening voltage-dependent calcium channels (VDCC), and lead to mitochondrial calcium overload by opening mitochondrial calcium channels and activating mitochondrial calcium uniporter (MCU). In addition, the activation of VDCC by inhalational anesthetics also triggers the release of Ca²⁺ from the endoplasmic reticulum (ER) by activating IP3 or ryanodine receptors on the ER membrane. The increase in cytosolic calcium, on one hand, exacerbates neuroinflammation through CaN-mediated mitochondrial retrograde signaling, and on the other hand, exacerbates mitochondrial calcium overload. Mitochondrial calcium overload mediates the opening of the mitochondrial permeability transition pore (mPTP), leading to a decrease in mitochondrial membrane potential (MMP) and the release of cytochrome C, inducing mitochondrial dysfunction and neuronal apoptosis. Furthermore, calcium overload leads to increased ROS production, activation of the NLRP3 inflammasome, and decreased ATP production, further exacerbating neuroinflammation and mitochondrial dysfunction

Fig. 3

The role and mechanism of mitochondrial iron homeostasis imbalance in POCD. General anesthesia upregulates the expression of NMDAR, leading to mitochondrial iron overload by enhancing DMT1-mediated iron uptake and lysosomal iron release. Surgery can increase divalent metal transporter 1 and hepcidin, and decrease transferrin receptor and ferroportin 1, thereby causing iron overload. Mitochondrial iron homeostasis imbalance leads to reduced ATP production, increased ROS production through TCA and glucose metabolism pathways, and ultimately leads to mitochondrial dysfunction and POCD. Iron overload can also lead to pro-inflammatory activation of microglia, exacerbating neuroinflammation. In addition, iron metabolism abnormalities caused by general anesthesia can lead to the occurrence of POCD by promoting neuronal ferroptosis

Fig. 4

The role and mechanism of mitochondrial oxidative stress in POCD. After surgical and anesthetic exposure, mitochondria are not only the main source of ROS generation but also the main target of oxidative damage. Oxidative damage leads to mitochondrial dysfunction, such as decreased mitochondrial membrane potential (MMP), mtDNA release, impaired respiratory chain, and reduced ATP production. In addition, the activation of the integrated stress response (ISR) regulates oxidative stress through mitochondria, and excessive ISR can lead to mitochondrial energy imbalance and respiratory chain dysfunction, further increasing the release of mtROS. The increased production of mtROS exacerbates neuronal damage and the occurrence of POCD through a crosstalk with neuroinflammation