Brinkkötter, Paul - CAP 1

Mitochondrial dysfunction and glomerular disease

The terminally differentiated podocyte is a critical component of the glomerular filtration barrier. Loss of podocytes contributes to the development of kidney diseases resulting in proteinuria and glomerulosclerosis. In this project we investigated the role of prohibitins in glomerular podocytes, characterized a link between insulin signaling and prohibitin function and identified an extra-mitochondrial function of prohibitin-1/-2 at the kidney filtration barrier.


Diseases of the kidney filtration barrier are a leading cause of chronic kidney disease. The filtration barrier consists of three layers: the fenestrated endothelium of the vasculature, the glomerular basement barrier (GBM) and the highly differentiated podocytes. The latter are solely attached to the GBM. The severity and reversibility of any glomerular disease is defined by the degree of podocyte injury. Loss of podocytes, due to apoptosis or detachment from the glomerular basement membrane, leads to glomerular scarring and to the development of kidney failure.

Our work focuses on the function of podocytes in states of health and disease with special emphasis on signaling pathways. There are several lines of evidence proposing an important role of mitochondriae to maintain podocyte function comprising respiratory chain activity and ATP production, inhibition of intrinsic apoptosis pathways and potentially buffering cytosolic Ca2+ release.

Mitochondrial dysfunction and podocyte disease

Mitochondrial dysfunction and alterations in energy metabolism have been implicated in a variety of human diseases. Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin-2 (PHB2) at the mitochondrial inner membrane. We generated podocyte-specific Phb2 knockout mice (Phb2pko) using a conditional Phb2 allele as a model of dysfunctional mitochondriae. Mice of all genotypes were born in predicted Mendelian frequency. Phb2pko mutants appeared as healthy as their littermate controls at birth. By 3 weeks of age proteinuria and growth restriction became evident in Phb2pko mice. By 4-5 weeks of age, complete destruction of the glomerular tuft was observed accompanied by progressive proteinuria, glomerulosclerosis and endstage renal failure. Mitochondria appeared disorganized with multiple swollen cristae structure.

We provided a link between PHB2 deficiency and hyperactive insulin/IGF-1 signaling. Deletion of PHB2 in podocytes resulted in hyper-phosphorylation of S6 ribosomal protein (S6RP), a known mediator of the mTOR signaling pathway. Inhibition of the insulin/IGF-1 signaling system through genetic deletion of insulin receptor alone or in combination with the IGF-1 receptor or treatment with rapamycin prevented hyper-phosphorylation of S6RP alleviated renal disease and delayed the onset of kidney failure in PHB2 deficient animals without affecting the mitochondrial structural defect. Of note, despite its beneficial role on animal survival and renal function, inhibition of the insulin/IGF-1 signaling cascade did not prevent the onset and magnitude of proteinuria. Hence, perturbation of insulin/IGF-1 receptor signaling contributes to tissue damage in mitochondrial disease, which may allow therapeutic intervention against a wide spectrum of glomerular diseases.

Additional immunogold labeling and EM studies in mice as well as studies in the nematode C. elegans suggest additional, non-mitochondrial function of PHB-2 in podocytes that could explain the severely damaged filtration barrier.


Clinical and experimental evidence emphasizes the mitochondrial impact on podocyte function. Within this research project we will provide further mechanistic insights into the role of mitochondria with respect to oxidative phosphorylation (OXPHOS) and generation of ATP as well as mitochondrial signaling events in states of health and disease. We will further study the link between mitochondrial function and the insulin signaling pathway. The long-term perspective of this project is to determine the mitochondrial contribution to podocyte-driven glomerular disease and potentially characterize novel, drugable signaling pathways. We expect that our results will not only lead to a better understanding of glomerular diseases but also to important insights into mitochondrial physiology and insulin signaling in general.

Selected publications

Rinschen MM, Schroeter CB, Koehler S, Ising C, Schermer B, Kann M, Benzing T, Brinkkoetter PT. Quantitative deep mapping of the cultured podocyte proteome uncovers shifts in proteostatic mechanisms during differentiation. Am J Physiol Cell Physiol. 2016 Sep 1;311(3):C404-17.

Koehler S, Tellkamp F, Niessen CM, Bloch W, Kerjaschki D, Schermer B, Benzing  T, Brinkkoetter PT. Par3A is dispensable for the function of the glomerular filtration barrier of the kidney. Am J Physiol Renal Physiol. 2016 Jul 1;311(1):F112-9.

Ising C, Bharill P, Brinkkoetter S, Brähler S, Schroeter C, Koehler S, Hagmann H, Merkwirth C, Höhne M, Müller RU, Fabretti F, Schermer B, Bloch W, Kerjaschki D, Kurschat CE, Benzing T, Brinkkoetter PT. Prohibitin-2 Depletion Unravels Extra-Mitochondrial Functions at the Kidney Filtration Barrier. Am J Pathol. 2016 May;186(5):1128-39.

Brähler S, Ising C, Barrera Aranda B, Höhne M, Schermer B, Benzing T, Brinkkoetter PT. The NF-κB essential modulator (NEMO) controls podocyte cytoskeletal dynamics independently of NF-κB. Am J Physiol Renal Physiol. 2015 Oct 1;309(7):F617-26.

Ising C, Koehler S, Brähler S, Merkwirth C, Höhne M, Baris OR, Hagmann H, Kann M, Fabretti F, Dafinger C, Bloch W, Schermer B, Linkermann A, Brüning JC, Kurschat CE, Müller RU, Wiesner RJ, Langer T, Benzing T, Brinkkoetter PT. Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure. EMBO Mol Med. 2015 Feb 2.

Rinschen MM, Pahmeyer C, Pisitkun T, Schnell N, Wu X, Maaß M, Bartram MP, Lamkemeyer T, Schermer B, Benzing T, Brinkkoetter PT. Comparative Phosphoproteomic analysis of mammalian glomeruli reveals conserved podocin C-terminal phosphorylation as a determinant of slit diaphragm complex architecture. Proteomics. 2014 Nov 25.

Koehler S, Brähler S, Braun F, Hagmann H, Rinschen MM, Späth MR, Höhne M, Wunderlich FT, Schermer B, Benzing T, Brinkkoetter PT. A T2A-peptide based knock-in mouse model for enhanced Cre recombinase activity and fluorescent labeling of podocytes. Kidney International Kidney Int. 2017 Feb 7.

Koehler S, Brähler S, Binz J, Hackl M, Hagmann H, Kuczkowski A, Vogt M, Wunderlich C, Wunderlich T, Schweda F, Schermer B, Benzing T, Brinkkoetter PT. A Single and Transient Ca2+ Wave in Podocytes does not induce Changes in Glomerular Filtration and Perfusion. Sci Rep. 2016 Oct 19;6:35400.

Former Funding Period 01/2014 - 12/2016

Information from this funding period will not be updated anymore. New research related information is available here.

Prof. Dr. med. Paul T Brinkkötter

Dept. II of Internal Medicine

Prof. Dr. med. Paul T Brinkkötter

Work +49 221 478 89593

Dept. II of Internal Medicine Nephrology, Rheumatology, Diabetology and general Internal Medicine
Kerpener Str. 62
50937 Cologne


Link to PubMed

Group Members

Sybille Köhler (PhD, PostDoc)
Henning Hagmann
(MD, PostDoc)
Alexander Kuczkowski (MD, PostDoc)
Angelika Köser (technician)
Nicole Mangold (MD student)
Kristina Schönfelder (MD student)
Christina Schroeter (MD student)

Figure 1

Fig.1: Podocytes of wild type mice have healthy mitochondria with normal cristae structures (left), whereas podocytes of PHB2 knockout mice contain mitochondria with disorganized and swollen cristae structures (right).

Figure 2

Fig.2: Genetic deletion of both, insulin receptor and IGF-1 receptor in addition to PHB2 (Phb2pko/Insrpko/Igf1rpko) significantly alleviated renal disease and enhanced survival as compared to Phb2pko mice.

Figure 3

Fig.3: PHB-2::GFP and MEC-2 overlap along touch punctae of the touch receptor neurons (A). PHB-2 deficient worms showed a significantly reduced number of touch responses. mec-2 and mev-1 knockdown served as controls (B).