Targeting aldehyde dehydrogenase 2: new therapeutic opportunities

Abstract

A family of detoxifying enzymes called aldehyde dehydrogenases (ALDHs) has been a subject of recent interest, as its role in detoxifying aldehydes that accumulate through metabolism and to which we are exposed from the environment has been elucidated. Although the human genome has 19 ALDH genes, one ALDH emerges as a particularly important enzyme in a variety of human pathologies. This ALDH, ALDH2, is located in the mitochondrial matrix with much known about its role in ethanol metabolism. Less known is a new body of research to be discussed in this review, suggesting that ALDH2 dysfunction may contribute to a variety of human diseases including cardiovascular diseases, diabetes, neurodegenerative diseases, stroke, and cancer. Recent studies suggest that ALDH2 dysfunction is also associated with Fanconi anemia, pain, osteoporosis, and the process of aging. Furthermore, an ALDH2 inactivating mutation (termed ALDH2*2) is the most common single point mutation in humans, and epidemiological studies suggest a correlation between this inactivating mutation and increased propensity for common human pathologies. These data together with studies in animal models and the use of new pharmacological tools that activate ALDH2 depict a new picture related to ALDH2 as a critical health-promoting enzyme.

FIGURE 1.

Ethanol metabolism. A: ethanol metabolism occurs in two steps: ethanol is metabolized quickly by alcohol dehydrogenase (ADH) to generate acetaldehyde. Acetaldehyde is then metabolized by the mitochondrial aldehyde dehydrogenase 2 (ALDH2) to acetate. The first step of metabolism, catalyzed by ADH, is a reversible reaction. The second step, catalyzed by ALDH2, is the rate-limiting step in ethanol metabolism, and it takes ∼1 h to metabolize the amount of ethanol that is found in a single alcoholic beverage. B: ethanol metabolism occurs mainly in the liver. In normal ALDH2 individuals, acetaldehyde is quickly oxidized to nontoxic acetate. In ALDH2 enzyme-deficient (ALDH2*2) individuals, a significant amount of acetaldehyde is rapidly accumulated even after a moderate amount of alcohol ingestion. Acetaldehyde, which is very diffusible and crosses biological membranes, can be circulated in the blood and metabolized in all tissues, as ALDH2 is present in all mitochondria.

FIGURE 2.

Alda-1, an allosteric agonist of ALDH2, corrects the structural defect in the ALDH2*2 mutant present in 8% of the human population. Top: crystal structure of Alda-1 (stick presentation) in the catalytic tunnel (shown as filled structure) of ALDH2 (Protein Data Bank Accession Code PDB: 3INJ). Highlighted are the critical amino acids in this interaction. Bottom: crystal structure of wild-type ALDH2 (left panel, Protein Data Bank Accession Code PDB: 1O05) and mutant ALDH2*2 (middle panel, Protein Data Bank Accession Code, PDB: 1ZUM). Co-crystal structure of ALDH2*2 with Alda-1 (shown as a ball-filled structure and highlighted in yellow; see arrows) is provided in the right panel (PDB: 3INL). Circles focus on the alpha helix structure (αG) that is missing in the mutant ALDH2*2 enzyme (middle panel vs. left panel) and is restored (right panel) when Alda-1 is bound to ALDH2*2. Images produced using UCSF Chimera package from the Computer Graphics Laboratory, University of California, San Francisco.

FIGURE 3.

4-HNE, an aldehydic product of lipid peroxidation, causes cytotoxicity. Buildup of aldehydes, such as 4-hydroxynonenal (4-HNE), due to oxidative stress promotes cell death. Listed are steps in aldehydic injury to cells, using 4-HNE (depicted as a zigzag line), as an example. 1) 4-HNE is produced through ROS-mediated lipid peroxidation of mitochondrial and plasma membranes. 4-HNE can in turn 2) reduce membrane integrity, 3) inhibit proteasomal function, 4) trigger unfolded protein accumulation, 5) inhibit electron transport chain activity, 6) reduce Kreb's cycle activity, 7) inhibit ALDH2 activity, 8) increase mitochondrial permeability and dysfunction, or 9) cause DNA damage.

FIGURE 4.

Diseases in which activators of ALDH2 may be beneficial. See text for full discussion. Red highlights diseases where the evidence for ALDH2 role came from preclinical proof-of-concept studies. Blue highlights diseases where ALDH2 role was supported by clinical observations. Black highlights diseases where evidence from both preclinical studies and from human epidemiological or pathohistological studies supports a role for ALDH2.

FIGURE 5.

Ethanol-induced cardiotoxicity. ALDH2 confers protection against ethanol toxicity by affecting the activity of key proteins in cardiac myocytes. The scheme summarizes data from transgenic mice that elucidated the potential pathways that are regulated by ALDH2 and acetaldehydes. Activation of ALDH2 or ALDH2 overexpression were found to confer cardiac protection by regulating autophagy and apoptosis through the balance between Akt and AMPK and their downstream substrates, such as mTOR, STAT3, Notch1, PP2A, and PP2C (93, 98, 112).

FIGURE 6.

ALDH2 and Fanconi anemia. In a mouse model of Fanconi anemia (FANCD), ALDH2 is essential in counteracting acetaldehyde toxicity. In the absence of a functional ALDH2, DNA damage triggered by elevated acetaldehyde toxicity cannot be repaired efficiently due to Fanconi mutations. Accumulation of such unrepaired damaged DNA leads to the manifestation of multiple pathological conditions and health complications seen also in patients with Fanconi anemia (95, 161, 244).