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Pyruvate kinase M2 activation maintains mitochondrial metabolism by regulating the interaction between HIF-1α and PGC-1α in diabetic kidney disease

Authors
 Jimin Park  ;  Young Su Joo  ;  Bo Young Nam  ;  Gyuri Kim  ;  Jung Tak Park  ;  Tae-Hyun Yoo  ;  Shin-Wook Kang  ;  Seung Hyeok Han 
Citation
 MOLECULAR MEDICINE, Vol.31(1) : 266, 2025-07 
Journal Title
MOLECULAR MEDICINE
ISSN
 1076-1551 
Issue Date
2025-07
MeSH
Animals ; Apoptosis ; Diabetic Nephropathies* / etiology ; Diabetic Nephropathies* / metabolism ; Diabetic Nephropathies* / pathology ; Disease Models, Animal ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit* / genetics ; Hypoxia-Inducible Factor 1, alpha Subunit* / metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria* / metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha* / genetics ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha* / metabolism ; Pyruvate Kinase* / metabolism
Keywords
Diabetic kidney disease ; Mitochondrial metabolism ; Pyruvate kinase M2
Abstract
Background: Pyruvate kinase isoform M2 (PKM2) activation has been suggested as a potential protective mechanism against kidney injury by improving mitochondrial dysfunction and anaerobic glycolysis. However, the underlying molecular mechanisms are unclear. Herein, we have demonstrated that PKM2 activation alleviates HIF-1α-mediated suppression of PGC-1α in diabetic kidney disease (DKD) models.

Methods: In animal DKD study, db/db mice were intraperitoneally injected with TEPP-46, a PKM2 activator. In vitro, primary cultured renal tubular epithelial cells (RTECs) from C57BL/6 mice were exposed to high glucose (HG) conditions with and without TEPP-46. The interaction between HIF-1α and PGC-1α was investigated using HIF-1α overexpression and suppression.

Results: Our findings in db/db mice kidneys unveiled a reduced PKM2 activation, aberrant glycolysis, impaired fatty acid oxidation, and decreased mitochondrial mass, integrity, and function under diabetic conditions. These changes were accompanied by increased HIF-1α and decreased PGC-1α levels. Furthermore, diabetic kidney exhibited increased fibrosis and apoptosis markers. Notably, direct PKM2 activation by TEPP-46 treatment counteracted the perturbed energy metabolism, restored mitochondrial function, and reduced cell death. Similar effects were also observed in HG-treated RTECs upon TEPP-46 intervention. Mechanistically, our chromatin immunoprecipitation assay revealed that HIF-1α directly bound to the regulatory region of the Ppargc1a promoter, and this interaction was inversely dependent on PKM2 activation. Moreover, Hif1ɑ overexpression suppressed Ppargc1a and triggered aberrant energy metabolism, mitochondrial dysfunction, and apoptosis. These changes were reversed by HIF-1α suppression.

Conclusion: Our study highlights the role of PKM2 activation in restoring impaired mitochondrial metabolism and function by modulating HIF-1α and PGC-1α interactions in DKD.
Files in This Item:
T202505361.pdf Download
DOI
10.1186/s10020-025-01320-4
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Shin Wook(강신욱) ORCID logo https://orcid.org/0000-0002-5677-4756
Park, Jung Tak(박정탁) ORCID logo https://orcid.org/0000-0002-2325-8982
Yoo, Tae Hyun(유태현) ORCID logo https://orcid.org/0000-0002-9183-4507
Joo, Young Su(주영수) ORCID logo https://orcid.org/0000-0002-7890-0928
Han, Seung Hyeok(한승혁) ORCID logo https://orcid.org/0000-0001-7923-5635
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/207182
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