ALDOB K87 Lactylation Regulates Mitochondrial Dynamics in Pulmonary Hypertension

Study Background and Research Question

Pulmonary hypertension (PH) is a progressive and often fatal cardiopulmonary disorder characterized by pulmonary vascular remodeling, occlusive arteriopathy, and eventual right ventricular failure. Current treatments primarily target vasodilation, but these approaches have only modest effects on survival and do not reverse the underlying vascular remodeling. Recent research has focused on the metabolic reprogramming of pulmonary artery smooth muscle cells (PASMCs), particularly the shift from oxidative phosphorylation to aerobic glycolysis (the Warburg effect), which supports abnormal cell proliferation and vascular pathology. However, the molecular bridges connecting metabolic changes to PASMC behavior in PH remain incompletely defined.

Key Innovation from the Reference Study

The reference study by Yi et al. (2026) (Communications Biology) introduces a novel molecular axis involving the lactylation of aldolase B (ALDOB) at lysine 87 (K87). This post-translational modification is shown to be a key modulator of mitochondrial fission and metabolic reprogramming in PASMCs under hypoxic conditions, providing a mechanistic link between elevated glycolytic flux, lactate accumulation, and the pathological proliferation of smooth muscle cells in PH.

Methods and Experimental Design Insights

The authors employed an integrated lactylomic profiling approach in both hypoxic human PASMCs and rodent models of PH. This involved mass spectrometry-based identification of lactylated proteins, with a focus on nonhistone targets. The most prominent modification detected was at the K87 site of ALDOB. Functional validation was performed using genetic and pharmacological manipulation of ALDOB lactylation, as well as the use of lactylation-mimetic mutants in vitro and in vivo.

Mechanistic experiments demonstrated that ALDOB K87 lactylation facilitates recruitment of dynamin-related protein 1 (DRP1) to mitochondria via sentrin/SUMO-specific peptidase 3–mediated deSUMOylation of DRP1, thereby promoting mitochondrial fragmentation. The team also investigated the role of sirtuin 1 as a delactylase and its downregulation in PH, which sustains ALDOB lactylation and the associated pathological effects.

Core Findings and Why They Matter

This study reveals several key findings:

• ALDOB K87 lactylation is significantly upregulated in hypoxic PASMCs and in rodent models of PH.
• Increased ALDOB lactylation amplifies glycolytic flux, creating a self-reinforcing cycle of lactate production and lactylation.
• ALDOB lactylation promotes mitochondrial fission by facilitating DRP1 recruitment and deSUMOylation, which in turn drives PASMC proliferation, migration, and phenotypic switching.
• Suppressing ALDOB lactylation, either genetically or pharmacologically, attenuates mitochondrial fission and limits PH progression in vivo.
• Lactylation-mimetic ALDOB mutants exacerbate mitochondrial fragmentation and vascular remodeling, confirming the causative role of this modification.

These results establish a lactate–ALDOB–DRP1 axis that directly connects metabolic reprogramming to the cellular processes underlying vascular remodeling in PH. The work shifts the paradigm from a purely metabolic or signaling perspective to one that integrates post-translational modifications as drivers of disease.

Comparison with Existing Internal Articles

Several recent reviews and analyses have discussed the role of metabolic remodeling and growth factors in pulmonary vascular disease. For instance, the article "ALDOB K87 Lactylation Drives Mitochondrial Fission in PH" highlights the mechanistic link between ALDOB lactylation and mitochondrial dynamics, echoing the findings of Yi et al. (2026). Complementary resources, such as "PDGF-BB, Murine Recombinant Protein: Mitogen Activity & Protocols", focus on the role of PDGF-BB as a mitogen in PASMC proliferation, providing practical assay parameters and workflow guidance for studying smooth muscle cell growth.

Notably, these internal articles outline how recombinant growth factors such as PDGF-BB can be used to model and dissect signaling pathways involved in vascular remodeling, thus creating a methodological bridge between molecular findings (such as ALDOB K87 lactylation) and functional cell proliferation assays ("Optimizing Cell Proliferation Assays with Murine Recombinant PDGF-BB").

Limitations and Transferability

Despite the depth of mechanistic insight, several limitations should be considered. The study primarily employs in vitro hypoxic PASMC models and rodent PH models, which, while informative, may not fully capture the complexity of human disease. The clinical relevance of targeting ALDOB lactylation in PH patients remains to be established, and the specificity of pharmacological inhibitors for ALDOB lactylation requires further validation. Additionally, the broader impact of ALDOB lactylation on other cell types within the pulmonary vasculature or in systemic metabolism has yet to be explored.

Transferability to other diseases characterized by metabolic rewiring and mitochondrial dynamics, such as cardiac hypertrophy or fibrotic disorders, is conceptually intriguing but unproven in the current literature. Caution is advised in generalizing these conclusions beyond the PH context without further evidence.

Protocol Parameters

• Hypoxic PASMC culture: Typically performed at 1% O₂ for 24–72 hours to induce metabolic reprogramming relevant to PH.
• Lactylomic profiling: Mass spectrometry-based identification of lactylated peptides, with sample preparation protocols optimized for nonhistone targets.
• Genetic manipulation: Use of CRISPR/Cas9 or siRNA for ALDOB knockdown or mutation at K87; lactylation-mimetic mutants generated by K87Q substitution.
• Pharmacological intervention: Application of small-molecule inhibitors or sirtuin 1 activators to modulate ALDOB lactylation status.
• Cell proliferation assays: For functional readouts, PDGF-BB is often used at effective concentrations below 2 ng/ml, as supported by product information and internal protocols.
• Mitochondrial fission assessment: Confocal microscopy of mitochondrial morphology, with DRP1 localization determined by immunofluorescence or subcellular fractionation.

Research Support Resources

For researchers interested in investigating smooth muscle cell proliferation and metabolic reprogramming in PH, robust in vitro assays are essential. The PDGF-BB, murine recombinant protein (SKU P1048) from APExBIO is validated for use in cell proliferation studies, with high purity and confirmed mitogen activity in murine BALB/c 3T3 cells. This reagent can support mechanistic experiments examining the interplay between growth factor signaling and metabolic modifications such as ALDOB lactylation. For full assay protocols and technical specifications, consult the product documentation.