Table 2 Autophagy-related influencing factors
From: Autophagy: a double-edged sword in ischemia–reperfusion injury
Pharmacological interventions | Mechanism | Refs. |
|---|---|---|
Rapamycin | Rapamycin serves as a highly effective and selective inhibitor of the mTOR signaling pathway, thereby promoting the process of autophagy | |
Empagliflozin | The SGLT2 inhibitor, empagliflozin, confers cardioprotection by mitigating autophagic cell death in cardiomyocytes, which is induced by excessive autophagy. Furthermore, empagliflozin alleviates ischemia/reperfusion injury in cardiac microvasculature through the activation of the AMPKα1/ULK1/FUNDC1/mitochondrial autophagy signaling pathway | |
Calcium channel inhibitors | The elevation of intracellular Ca2+ levels and the consequent swelling of mitochondria expedite the autophagic process | |
Carfilzomib (CFZ) | The administration of CFZ resulted in elevated levels of ubiquitinated BNIP3L and LC3B, thereby promoting autophagic activity | |
Overactivation of the mTOR pathway | In colorectal cancer, the hyperactivation of the mTOR signaling pathway can suppress the initiation of autophagy, consequently facilitating the proliferation and survival of tumor cells | [60] |
Genetic manipulation | ||
Circ-FoxO3 | Circ-FoxO3 facilitates the modulation of autophagy or ATG through knockout or overexpression by inhibiting mTORC1 | |
ncRNAs | In the context of spinal cord ischemia–reperfusion injury (SCIRI), noncoding RNAs (ncRNAs) have the capacity to regulate apoptosis, inflammation, autophagy, and oxidative stress, thereby mitigating the effects of SCIRI | [100] |
Beclin 1 | Beclin 1 modulates autophagy via phosphorylation, while the pro-apoptotic kinase Mst1 can suppress autophagy by phosphorylating the BH3 domain of Beclin 1 | |
ATG gene | The protein encoded by the ATG gene is integral to the initiation and nucleation of autophagosomes. Specifically, ATG1, in conjunction with the ULK1/2 complex, and ATG13 are pivotal during the early stages of autophagosome formation. They form complexes with ATG14 and FIP200, which facilitate the initiation of autophagosomes. ATG proteins engage in intricate interactions to form various complexes, such as the ATG5–ATG12–ATG16L1 complex and the ATG8 (LC3) lipid system. Notably, the lipidated form of LC3, known as LC3-II, serves as a hallmark of autophagosome formation. These complexes are crucial for the expansion of the autophagosome membrane and its subsequent fusion | |
Environmental factors | ||
H2S | Low concentrations of hydrogen sulfide (H2S) have the potential to mitigate neuronal damage induced by cerebral ischemia–reperfusion (CIR) | [104] |
BNIP3L | BNIP3 has been characterized as a pro-apoptotic protein, the induction of which has been demonstrated to enhance the insertion and activation of BAX (BCL2-associated X, apoptosis regulator) and BAK (BCL2 antagonist/killer 1) within the mitochondria | |
ULK1 | The phosphorylation of FUNDC1 by ULK1 has been demonstrated to activate FUNDC1-dependent mitophagy | |
PI3K | Phosphatidylinositol 3-kinase (PI3K)-activated protein kinase B (PKB) undergoes activation through direct phosphorylation of a pivotal component of the mTORC1. Phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3) can activate PKB, which subsequently inhibits autophagy by phosphorylating and suppressing the activity of mTOR. In contrast to class I PI3K, class III PI3K plays a crucial role in the initiation of autophagy. Class III PI3K generates PI3P, a critical step in the formation of autophagosomes. Additionally, PIP3 functions as a second messenger, modulating other signaling molecules and kinases, thereby exerting an indirect regulatory effect on autophagy | |
PINK1-Parkin | The PINK1-PRKN/Parkin pathway facilitates the tagging of impaired mitochondria with ubiquitin chains, thereby initiating their selective autophagic degradation | |
CL | Cardiolipin-mediated mitophagy triggers the initiation of mitophagy in response to cellular stress through the interaction between cardiolipin (CL) and microtubule-associated protein 1A/1B-light chain 3 (LC3) | |
Ceramides | Ceramides have the capacity to induce autophagy through multiple mechanisms. They activate intracellular signaling pathways, including ERK and p38 MAPK, which play a crucial role in the initiation of autophagy | [169] |
Hypoxia | Following hypoxic conditions, anaerobic glycolysis becomes the primary metabolic pathway, resulting in the accumulation of lactic acid and hydrogen ions, which in turn causes intracellular acidosis | |
Nutritional deprivation | Under conditions of nutrient deprivation, cells initiate the degradation of their own components, including damaged proteins, organelles, and other biological macromolecules, to facilitate the synthesis of new molecules or to serve as an energy source. Furthermore, nutrient deprivation results in decreased levels of intracellular amino acids and growth factors, thereby inhibiting the mTOR signaling pathway and promoting the induction of autophagy | |
NLRP3 inflammasomes | The activation of the NLRP3 inflammasome is induced by ROS and adenosine triphosphate (ATP), subsequently resulting in the secretion of the pro-inflammatory cytokines interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), as well as the initiation of pyroptosis | [174] |
Lysosomal clearance dysfunction | Lysosomal dysfunction can result in the accumulation of autophagic substrates within the cell, thereby impairing cellular function and potentially leading to cell death. Moreover, rupture or dysfunction of lysosomes may cause the release of their enzymes into the cytoplasm, which can initiate an inflammatory response and contribute to cellular demise | |
Ferroptosis | Ferroptosis is characterized by the accumulation of lipid ROS originating from iron metabolism, with its primary features being mitochondrial condensation and increased bilayer membrane density | |
Nrf2 | Nrf2 promotes the expression of antioxidant genes and, under nonstressed conditions, is sequestered in the cytoplasm through direct interaction with Keap1 | |
AMPK | Activated AMPK has the capability to mitigate oxidative stress by suppressing NADPH oxidase activity and enhancing antioxidant responses mediated by Nrf2 | [182] |