ArticleProceedings of the National Academy of Sciences of the United States of America2022
Noncanonical PDK4 action alters mitochondrial dynamics to affect the cellular respiratory status.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 49 citations in OpenAlex.
- Targeting Endothelial PDK4-EndoMT Feedback Loop Mitigates the Development of Thoracic Aortic Dissection in Mice.Arteriosclerosis, thrombosis, and vascular biology · 2026Article
- Heterogeneity of glucose metabolism and uptake identifies distinct cancer cell and cancer stem cell phenotypes.Cellular & molecular biology letters · 2026Article
- Dynamic imbalance of mitochondria-associated ER membranes in cardiovascular disease: mechanisms, context dependence and therapeutic potential.Frontiers in cell and developmental biology · 2026Review
- Extracellular matrix-driven metabolic control of pancreatic endocrine lineage allocation.EMBO reports · 2025Article
- Artesunate Nanoplatform Targets the Serine-MAPK Axis in Cancer-Associated Fibroblasts to Reverse Photothermal Resistance in Triple-Negative Breast Cancer.Advanced materials (Deerfield Beach, Fla.) · 2025Article
- Methods and Guidelines for Metabolism Studies: Applications to Cancer Research.International journal of molecular sciences · 2025Review
- Bezafibrate improves mitochondrial function, blood-brain barrier integrity, and social deficits in models of 22q11.2 deletion syndrome.Science translational medicine · 2025Article
- Pathogenic morphological signatures of perturbations in mitochondrial-related genes revealed by pooled imaging assay.Npj imaging · 2025Article
- The impact of ERCell death & disease · 2025Article
- Myocardial pyruvate dehydrogenase kinase 4 drives sex-specific cardiac responses to endotoxemia.JCI insight · 2025Article
- An evaluation of spraying as a delivery method for human mesenchymal stem cells suspended in low-methyl pectin solutions.Stem cell research & therapy · 2025Article
- Mitochondria at the Heart of Sepsis: Mechanisms, Metabolism, and Sex Differences.International journal of molecular sciences · 2025Review
- High-fat diet promotes lipotoxicity in the podocytes of uninephrectomized mice: a targeted lipidomics and kidney podocyte-specific analysis.Cell death discovery · 2025Article
- Twelve-hour ultradian rhythmic reprogramming of gene expression in the human ovary during aging.Journal of assisted reproduction and genetics · 2025Article
- SUCLG1 promotes aerobic respiration and progression in plexiform neurofibroma.International journal of oncology · 2025Article
- Effects of seven days' fasting on physical performance and metabolic adaptation during exercise in humans.Nature communications · 2025Article
- Mitochondrial pyruvate dehydrogenase phosphatase metabolism disorder in malignant tumors.Oncology research · 2025Review
- Sodium Phenylbutyrate Attenuates Cisplatin-Induced Acute Kidney Injury Through Inhibition of Pyruvate Dehydrogenase Kinase 4.Biomedicines · 2024Article
- PDK4-mediated metabolic reprogramming is a potential therapeutic target for neovascular age-related macular degeneration.Cell death & disease · 2024Article
- Inhibition of Pyruvate Dehydrogenase Kinase 4 Protects Cardiomyocytes from lipopolysaccharide-Induced Mitochondrial Damage by Reducing Lactate Accumulation.Inflammation · 2024Article
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Dynamic regulation of mitochondrial morphology provides cells with the flexibility required to adapt and respond to electron transport chain (ETC) toxins and mitochondrial DNA-linked disease mutations, yet the mechanisms underpinning the regulation of mitochondrial dynamics machinery by these stimuli is poorly understood. Here, we show that pyruvate dehydrogenase kinase 4 (PDK4) is genetically required for cells to undergo rapid mitochondrial fragmentation when challenged with ETC toxins. Moreover, PDK4 overexpression was sufficient to promote mitochondrial fission even in the absence of mitochondrial stress. Importantly, we observed that the PDK4-mediated regulation of mitochondrial fission was independent of its canonical function, i.e., inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Phosphoproteomic screen for PDK4 substrates, followed by nonphosphorylatable and phosphomimetic mutations of the PDK4 site revealed cytoplasmic GTPase, Septin 2 (SEPT2), as the key effector molecule that acts as a receptor for DRP1 in the outer mitochondrial membrane to promote mitochondrial fission. Conversely, inhibition of the PDK4-SEPT2 axis could restore the balance in mitochondrial dynamics and reinvigorates cellular respiration in mitochondrial fusion factor, mitofusin 2-deficient cells. Furthermore, PDK4-mediated mitochondrial reshaping limits mitochondrial bioenergetics and supports cancer cell growth. Our results identify the PDK4-SEPT2-DRP1 axis as a regulator of mitochondrial function at the interface between cellular bioenergetics and mitochondrial dynamics.
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