Table 3 The dual role of autophagy in ischemia–reperfusion injury in different organs

Heart

Autophagy serves as a critical cellular mechanism for mitigating oxidative stress and the accumulation of toxic substances by facilitating the removal of damaged organelles and proteins, thereby preserving intracellular homeostasis. Furthermore, moderate activation of autophagy is pivotal during the ischemia–reperfusion process in cardiomyocytes, contributing to the maintenance of cellular energy metabolism balance. Additionally, autophagy attenuates the release of inflammatory mediators through the clearance of damaged organelles, thus reducing further damage to cardiomyocytes and inhibiting the onset of inflammatory responses

In the context of myocardial IRI, excessive activation of autophagy may result in the degradation of critical organelles and proteins within cells, thereby compromising cellular structure and function, ultimately culminating in cell death. Autophagy is intricately linked to apoptosis, and during myocardial IRI, there is typically a reduction in mTOR activity accompanied by an upregulation of Beclin1 expression. This dynamic fosters the activation of both autophagy and apoptosis, thereby exacerbating cardiomyocyte damage

The role of mitochondrial autophagy in cardiac IRI is nuanced. A moderate level of mitochondrial autophagy facilitates the removal of damaged mitochondria, thereby mitigating mitochondrial damage and conferring protection to cardiomyocytes. Conversely, excessive activation of mitophagy can result in a substantial depletion of mitochondria, adversely impacting the energy metabolism of cardiomyocytes

[219,220,221]

Kidney

In the context of mild IRI, autophagy plays a protective role by mitigating the release of inflammatory cytokines through the removal of damaged organelles and proteins, thereby attenuating the inflammatory response and subsequent damage to renal cells. Within a specific threshold, autophagy serves to protect renal tubular cells by inhibiting apoptosis

In cases of severe IRI, excessive activation of autophagy can compromise essential organelles and proteins within kidney cells, potentially facilitating apoptosis and exacerbating cellular injury. This overactivation may undermine the structural integrity of kidney cells and promote apoptosis through various mechanisms, leading to an intensification of apoptosis that further exacerbates cellular damage and significantly impairs renal function

Mitophagy plays a critical role in the selective removal of damaged mitochondria, primarily through mechanisms such as the PINK1/Parkin pathway. This process not only reduces the production of reactive oxygen species (ROS) but also facilitates mitochondrial degradation via the autophagy pathway, thereby mitigating kidney damage. Under conditions of endoplasmic reticulum stress, the activation of the PERK and IRE1 pathways enhances autophagosome formation, aiding in the clearance of misfolded proteins and reducing cellular damage associated with endoplasmic reticulum stress

[138, 222, 223]

Liver

During ischemia–reperfusion, the energy supply to hepatocytes is significantly constrained. In such scenarios, moderate autophagy is crucial for maintaining cell viability by degrading intracellular components to provide energy. Furthermore, autophagy contributes to the removal of damaged mitochondria and proteins, thereby reducing oxidative stress and cellular damage, ultimately exerting a protective effect on liver cells

In instances of severe IRI, excessive activation of autophagy can result in the degradation of critical intracellular organelles and proteins, thereby compromising the structural and functional integrity of the cell and ultimately inducing cell death. This phenomenon holds significant importance in the pathological mechanisms underlying cellular injury, indicating that therapeutic approaches for IRI should focus on the precise modulation of autophagy to prevent further cellular damage due to its overactivation

Beyond the regulation of endoplasmic reticulum stress and mitophagy, microRNAs (miRNAs) are also pivotal in modulating autophagy in hepatic IRI. For instance, miR-17 exacerbates the pathological damage associated with IRI by enhancing autophagic activity. This suggests a potential regulatory role in the pathogenesis and progression of hepatic IRI, highlighting miR-17 as a prospective therapeutic target for the treatment of hepatic IRI in the future

[224, 225]

Brain

Physiological levels of autophagy play a protective role in neuronal cells by inhibiting apoptotic processes. For instance, pharmacological agents that stimulate autophagy, such as spermine, enhance autophagic activity through the activation of the AMPK/mTOR/ULK1 signaling pathway, thereby mitigating inflammation and apoptosis. Additionally, autophagy facilitates the recovery of neural tissue following ischemic events by modulating microglial phenotypic changes and engaging the NF-κB pathway

Following ischemic brain injury, excessive activation of autophagy can impair neuronal function, resulting in neurological deficits such as impaired learning and memory, as well as motor dysfunction

Consequently, modulating autophagy activity holds promise for mitigating neurological deficits post-ischemic brain injury and offers novel insights and targets for clinical interventions

[226,227,228]

Eye

In the context of retinal IRI (RIRI), autophagy plays a crucial role in mitigating oxidative stress damage by facilitating the removal of damaged mitochondria and decreasing the production of reactive oxygen species (ROS). Research indicates that modulating autophagic activity can significantly enhance the survival rate of retinal ganglion cells following ischemia–reperfusion. This suggests that autophagy not only alleviates oxidative stress through the clearance of damaged organelles but may also confer a protective effect by modulating inflammatory responses and apoptosis pathways

In cases of severe IRI in the eye, autophagy may be markedly activated, potentially leading to retinal dysfunction. For instance, 3-methyladenine (3-MA), a well-established autophagy inhibitor, has been shown to mitigate retinal IRI by curbing autophagy overactivation. Thus, 3-MA presents potential therapeutic value in treating retinal IRI, offering a viable strategy for inhibiting excessive autophagy

Inhibition of autophagic activity in rat models has been shown to reduce LC3-II levels, thereby diminishing the neuroprotective effects of ischemic posttreatment and exacerbating histological damage to the omentum. These findings imply that autophagy exhibits a complex dual role in retinal IRI, and precise regulation of autophagic activity is pivotal for achieving neuroprotection in the treatment of this condition

[229, 230]