ALDH2 in autophagy and cell death: molecular mechanisms and implications for diseases

Abstract

Aldehyde dehydrogenase (ALDH) 2, a mitochondrial enzyme, is the main acetaldehyde dehydrogenase involved in the scavenging of alcohol-derived acetaldehyde and endogenous aldehydes. The ALDH2^rs671 mutation affects 560 million East Asians and is closely related to an increased risk of various human diseases. In addition to its well-known function in detoxifying alcohol-derived acetaldehyde and endogenous aldehydes, ALDH2 is implicated in human health through its regulation of autophagic machinery and multiple cell death pathways (e.g., apoptosis, necroptosis, pyroptosis, ferroptosis, and NETosis). This review summarizes the current knowledge of ALDH2 and the regulatory mechanism through which ALDH2 regulates autophagy and cell death. In addition, we outline the potential role of ALDH2 in the regulation of autophagy and cell death during the occurrence and progression of human diseases, aiming to provide a novel theoretical framework for human disease treatment.

Keywords: Aldehyde dehydrogenase (ALDH) 2; Autophagy; Cell death; Human diseases.

Fig. 1

ALDH architecture. a Three conserved domains in an ALDH monomer (mouse): catalytic (purple), NAD(P) binding (yellow), and oligomerization (blue). b Homotetrameric structure of ALDH2 (mouse), individual subunits are rendered in different colors (yellow, purple, pink, green). c Three conserved domains in an ALDH monomer (human): catalytic (purple), NAD(P) binding (yellow), and oligomerization (green). d Homotetrameric structure of ALDH2 (human), individual subunits are rendered in different colors (yellow, purple, red, green). ALDH aldehyde dehydrogenase, NAD⁺ nicotinamide adenine dinucleotide

Fig. 2

ALDH2 in autophagy. ALDH2 initiates autophagy by phosphorylating AMPK and inhibiting mTOR activation. ALDH2 promotes the ULK1 phosphorylation to initiate autophagy. ALDH2 facilitates Akt phosphorylation and promotes mTOR activation to suppress autophagy. ALDH2 upregulates the expression of BECN1 and releases BECN1 from the complex to promote autophagy. AMPK phosphorylates ALDH2^rs671 and promotes its nuclear translocation. In turn, ALDH2^rs671 binds to HDAC3 to suppress ATP6V0E2 transcription and inhibit autophagic fusion. ALDH2 promotes FUNDC1-mediated mitophagy via Nrf1. ALDH2 activation allows mtDNA leakage into the cytosol, activating the cGAS-STING-TBK1 pathway to promote mitophagy. ALDH2 initiates mitophagy or inhibits excessive mitophagy activation through the PINK-PRKN pathway. ALDH2 inhibits mitophagy by inhibiting the CaMKII-DRP1 axis. ALDH2 interacts with PHB2 to inhibit its proteasomal degradation, thereby promoting mitophagy. Akt threonine-serine protein kinase B, ALDH2 aldehyde dehydrogenase 2, AMPK AMP-activated protein kinase, ATG autophagy-related, ATP6V0E2 ATPase H⁺ Transporting V0 Subunit E2, BCL2 B-cell lymphoma 2, BECN1 Beclin1, CaMKII Calmodulin-dependent kinase II, cGAS Cyclic guanosine monophosphate-adenosine monophosphate synthase, DRP1 dynamin-related protein 1, FUNDC1 FUN14 domain containing 1, HDAC3 histone deacetylase 3, LC3-PE microtubule-associated protein Light chain 3-Phosphatidylethanolamine, mTOR mechanistic target of rapamycin, Nrf1 nuclear respiratory factor 1, PHB2 Prohibitin 2, PINK PTEN-induced putative kinase 1, PRKN parkin RBR E3 ubiquitin protein ligase, RAB7 ras-related protein Rab-7a, SNAP29 synaptosomal-associated protein of 29 kD, STING stimulator of interferon genes, TBK1 TanK-binding kinase 1, ULK Unc-51-like kinase, VPS vacuolar protein sorting

Fig. 3

ALDH2 in apoptosis. a ALDH2 inhibits excessive mitophagy to suppress apoptosis through the PINK-PRKN pathway. ALDH2 activates the STING-TBK1 pathway or promotes the Nrf-FUNDC1 axis to initiate mitophagy, thereby inhibiting apoptosis. b ALDH2 maintains mitochondrial integrity and reduces ROS to prevent apoptosis. ALDH2 enhances BECN1 expression and release to promote autophagy, thereby reducing ROS and apoptosis. c ALDH2 elevates mitochondrial membrane potential to promote mitofusion (MFN) and suppress apoptosis. ALDH2 inhibits 4-HNE accumulation and excessive mitofission, alleviating apoptosis. ALDH2 suppresses apoptosis via PI3K/Akt/mTOR-mediated MFN2 upregulation and DRP1 downregulation. d ALDH2-PGC-1α axis promotes mitobiogenesis and inhibits apoptosis. ALDH2 activates Trx-1/AMPK/PGC-1α pathway to enhance mitobiogenesis and inhibit apoptosis. e ALDH2 blocks 4-HNE-induced PERK/eIF2α/ATF4 activation to alleviate ER stress and apoptosis. ALDH2 inhibits the IREα/XBP-1 pathway or upregulates GRP78 expression to inhibit ER stress-related apoptosis. MiR-193b-3p promotes apoptosis via ALDH2 inhibition and ER stress activation f ALDH2 suppresses apoptosis by inhibiting PI3K/Akt/NF-κB and STING pathways. ALDH2 blocks 4-HNE-induced JNK/p53 activation to suppress apoptosis. DSCR1-1 enhances ALDH2 transcription via CREB1 nuclear translocation, leading to inhibition of Wnt/β-catenin signaling and apoptosis suppression. g ALDH2-Rac2 axis enhances efferocytosis by inhibiting Rac2 degradation. 4-HNE 4-hydroxy-2-nonenal, Akt threonine-serine protein kinase B, ALDH2 aldehyde dehydrogenase 2, AMPK AMP-activated protein kinase, ATF4/6 Activating transcription factor 4/6, ATP6V0E2 ATPase H⁺ Transporting V0 Subunit E2, BCL2 B-cell lymphoma 2, BECN1 Beclin1, cGAS Cyclic guanosine monophosphate-adenosine monophosphate synthase, CHOP C/EBP homologous protein, CREB1 cAMP-responsive element protein 1, DRP1 dynamin-related protein 1, DSCR1-1 down syndrome candidate region 1–1, eIF2α eukaryotic initiation factor 2 alpha, ER endoplasmic reticulum, FUNDC1 FUN14 domain containing 1, GRP78 glucose-regulating protein 78, IREα inositol requiring kinase 1α, JNK c-Jun N-terminal kinase, LC3-PE microtubule-associated protein Light chain 3-phosphatidylethanolamine, mTOR mechanistic target of rapamycin, NF-κB nuclear factor kappa B, Nrf1 nuclear respiratory factor 1, PERK Pancreatic ER kinase (PKR)-like ER kinase, PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1 alpha, PI3K phosphatidylinositol 3-kinase, PINK PTEN-induced putative kinase 1, PRKN parkin RBR E3 ubiquitin protein ligase, Rac1 ras-related C3 botulinum toxin substrate, ROS reactive oxygen species, STING stimulator of interferon genes, TBK1 TanK-binding kinase 1, TFAM mitochondrial transcription factor A, Trx-1 thioredoxin-1, ULK Unc-51-like kinase, Wnt wingless and int-1, XBP-1 X-box binding protein-1

Fig. 4

ALDH2 in necroptosis, pyroptosis, ferroptosis, and NETosis. a ALDH2 reduces ROS to suppress necroptosis. ALDH2 blocks 4-HNE-induced necroptosis by promoting RIPK1 degradation. ALDH2 blocks HDAC3 mitochondrial translocation and subsequent HADHA deacetylation, suppressing the ROS-mtDNA-NLRP3 axis to attenuate pyroptosis. ALDH2 reduces ROS to suppress both BCL2-CASP3-GSDME and NLRP3-CASP1-GSDMD-mediated pyroptosis. b ALDH2 activates ERK/CREB1 signaling to upregulate GPX4 and ALDH2 expression, thereby inhibiting ferroptosis. ALDH2 suppresses ACSL4 expression by inhibiting SP1 activation to attenuate ferroptosis. ALDH2 mitigates ferroptosis via ROS reduction and lipid droplet biogenesis. ALDH2 counteracts 4-HNE-induced GPX4 degradation by preserving the GPX4-OTUD5 interaction, thereby inhibiting ferroptosis. c ALDH2-CHIP interaction inhibits NETosis by promoting PAD4 degradation. ALDH2 suppresses NETosis via ER stress-MGST2-LTC4-NOX2 cascade. 4-HNE 4-hydroxy-2-nonenal, ALDH2 aldehyde dehydrogenase 2, ACSL4 Acyl-CoA synthetase Long-chain family member 4, BCL2 B-cell lymphoma 2, CASP1/3 caspase 1/3, CHIP C-terminus of HSC70-interacting protein, CREB1 cAMP-responsive element protein 1, ER endoplasmic reticulum, ERK extracellular signal-regulated kinase, GSDMD gasdermin-D, GSDME gasdermin-E, HADHA hydroxyl-CoA dehydrogenase alpha subunit, HDAC3 histone deacetylase 3, GPX4 glutathione peroxidase 4, LTC4 leukotriene C4, MGST2 microsomal glutathione S-transferase 2, MLKL mixed lineage kinase domain-like protein, mtDNA mitochondrial DNA, NLRP3 nucleotide-binding domain (NBD), leucine-rich repeat (LRR), and pyrin, NOX4 NADPH oxidases 4, OTUD5 ovarian tumor (OTU) deubiquitinase 5, PAD4 peptidylarginine deiminase 4, RIPK1/3 receptor-interacting protein kinase 1/3, ROS reactive oxygen species, SP1 specificity protein 1

Fig. 5

ALDH2 regulates autophagy and cell death in cardiovascular diseases. Summarizing the type of cell death and autophagy in cardiovascular diseases. ALDH2 aldehyde dehydrogenase 2, I/R ischemia/reperfusion

Fig. 6

The effect of ALDH2-regulated autophagy and cell death in human diseases. Functional ALDH2-regulated autophagy and cell death are involved in various human diseases, with a protective effect or an adverse effect. ALDH2 aldehyde dehydrogenase 2