Universität zu Köln

Özel, Cem ORCID: 0009-0006-7091-7027, Reitmeier, Katrin M. ORCID: 0009-0003-8534-520X, Kieckhöfer, Emilia ORCID: 0009-0004-7888-9185, Abualia, Khawla ORCID: 0000-0002-7534-4014, Nguyen‐Minh, Duc, Matin, Mahsa ORCID: 0000-0001-7954-6863, Hagmann, Henning ORCID: 0000-0002-2624-2740, Coward, Richard J. M. ORCID: 0000-0001-6183-2546, Brähler, Sebastian, Antczak, Philipp ORCID: 0000-0001-9600-7757, Schermer, Bernhard ORCID: 0000-0002-5194-9000, Benzing, Thomas ORCID: 0000-0003-0512-1066, Giavalisco, Patrick ORCID: 0000-0002-4636-1827 and Brinkkoetter, Paul T. ORCID: 0000-0002-4287-2080 (2025). Disruption of Mitochondrial Dynamics and Integrity Drives Divergent Metabolic Flexibility and Resilience in Podocytes. The FASEB Journal, 39 (24). pp. 1-18. Wiley. ISSN 0892-6638

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Abstract

[Artikel-Nr.: e71340] Mitochondrial dysfunction is central to the pathogenesis of podocytopathies, yet the determinants of metabolic resilience versus failure remain elusive. We investigated how distinct disruptions of mitochondrial architecture, specifically hyperfusion via OMA1 deletion versus compromised inner mitochondrial membrane (IMM) integrity via PHB2 knockdown, influence the metabolic fate and insulin responsiveness of podocytes. To this end, we analyzed conditionally immortalized mouse podocytes with genetic OMA1 deletion or inducible PHB2 knockdown and employed an integrated approach combining bioenergetic studies, quantitative proteomics, phosphoproteomics, metabolomics, and stable isotope tracing studies with 13C6-glucose and 13C5-glutamine. We characterized metabolic remodeling at baseline and after insulin treatment and uncovered profoundly divergent metabolic states. OMA1 deficiency conferred robust metabolic resilience, characterized by a compensatory glycolytic shift and remodeling of TCA cycle flux through glutamine-driven anaplerosis while maintaining oxidative phosphorylation. OMA1-deficient podocytes sustained bioenergetic homeostasis upon insulin challenge by flexibly rerouting carbon flux, including the GABA shunt. In contrast, PHB2 deficiency led to metabolic failure, impaired respiration, and anaplerotic insufficiency. While maintaining basal ATP levels at baseline, PHB2-deficient podocytes exhibited energetic collapse upon insulin treatment, revealing profound metabolic inflexibility. Taken together, the structural integrity of the inner mitochondrial membrane, rather than mitochondrial morphology per se, is a driving determinant of metabolic competence and resilience in podocytes.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Özel, Cem UNSPECIFIED https://orcid.org/0009-0006-7091-7027 UNSPECIFIED Reitmeier, Katrin M. UNSPECIFIED https://orcid.org/0009-0003-8534-520X UNSPECIFIED Kieckhöfer, Emilia UNSPECIFIED https://orcid.org/0009-0004-7888-9185 UNSPECIFIED Abualia, Khawla UNSPECIFIED https://orcid.org/0000-0002-7534-4014 UNSPECIFIED Nguyen‐Minh, Duc UNSPECIFIED UNSPECIFIED UNSPECIFIED Matin, Mahsa UNSPECIFIED https://orcid.org/0000-0001-7954-6863 UNSPECIFIED Hagmann, Henning UNSPECIFIED https://orcid.org/0000-0002-2624-2740 UNSPECIFIED Coward, Richard J. M. UNSPECIFIED https://orcid.org/0000-0001-6183-2546 UNSPECIFIED Brähler, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Antczak, Philipp UNSPECIFIED https://orcid.org/0000-0001-9600-7757 UNSPECIFIED Schermer, Bernhard UNSPECIFIED https://orcid.org/0000-0002-5194-9000 UNSPECIFIED Benzing, Thomas UNSPECIFIED https://orcid.org/0000-0003-0512-1066 UNSPECIFIED Giavalisco, Patrick UNSPECIFIED https://orcid.org/0000-0002-4636-1827 UNSPECIFIED Brinkkoetter, Paul T. UNSPECIFIED https://orcid.org/0000-0002-4287-2080 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-813045
Identification Number:	10.1096/fj.202502934R
Journal or Publication Title:	The FASEB Journal
Volume:	39
Number:	24
Page Range:	pp. 1-18
Number of Pages:	18
Date:	31 December 2025
Publisher:	Wiley
ISSN:	0892-6638
Language:	English
Faculty:	External institution Faculty of Medicine
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing Faculty of Medicine > Innere Medizin > Klinik II für Innere Medizin - Nephrologie, Rheumatologie, Diabetologie und Allgemeine Innere Medizin
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language anaplerosis ; glycolysis ; insulin signaling ; metabolism ; mitochondria ; OMA1 ; PHB2 ; podocytes English
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81304