Paul T Brinkkötter - C 5

Mitochondrial energetics and its contribution to podocyte function

Metabolic signallin pathways orchestrate the dynamic turnover between catabolic and anabolic processes. Glomerular podocytes, which are part of the kidney filtration barrier, are thought to be highly energy demanding cells maintaining a highly dynamic actin cytoskeleton. Here, we will investigate the role of mitochondria in podocytes and (i) characterize how mitochondria regulate insulin signallin and (ii) identify the role of the respiratory chain for podocyte function in states of health and glomerular disease. 


The majority of kidney diseases affect the renal filtration unit, the glomerulus, as a consequence of a very limited capacity for regeneration and self-renewal of terminally differentiated glomerular podocytes. Podocytes are epithelial cells that have interdigitating foot processes to cover the outer surface of glomerular capillaries and to form filtration slits. They are essential components of the kidney filtration unit and responsible for ultrafiltration of protein-free urine from plasma. 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 apoptotic pathways and, potentially, buffering cytosolic Ca2+ release. 

Linking mitochondria to insulin signallin

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. Recently, we provided a link between PHB2 deficiency and hyperactive insulin/IGF-1 signallin. Deletion of PHB2 in murine podocytes caused progressive proteinuria, kidney failure and premature death of the animals. Inhibition of the insulin/IGF-1 signallin system through genetic deletion of the insulin receptor alone or in combination with the IGF-1 receptor or treatment with the mTOR inhibitor rapamycin prevented hyper-phosphorylation of S6RP without affecting the mitochondrial structural defect. Moreover, renal disease was found to be alleviated and the onset of kidney failure was delayed in PHB2 deficient animals. PHB2 function relies in parts on the activity of the protease OMA1 which cleaves OPA thereby promoting the mitochondrial fission machinery. Within this funding period, we generated PHB2/OMA1 double-knockout podocytes to further characterize the link between prohibitin function and insulin signalling. In contrast to neuronal cells where an additional knock-out of OMA1 in PHB2 deficient cells alleviated the disease phenotype, no effect on podocytes was observed (Figure 1). 

Moreover, single OMA1 knockout animals also showed increased insulin signalling and activation of mTOR in the absence of any disease phenotype further highlighting the importance of mitochondria and the control of insulin signalling (Figure 2). Interestingly, OMA1 single knockout animals did not develop podocyte disease favouring the hypothesis that PHB1/2 may confer additional, potentially extra-mitochondrial functions in podocytes.

To which extent do podocytes rely on mitochondrial respiration?

The mitochondrial transcription factor A (TFAM) is required for transcription and maintenance of mtDNA encoding for 13 mtDNA proteins. Depletion of Tfam leads to severe mitochondrial dysfunction of four out of five inner membrane oxidative phosphorylation complexes rendering the cells completely dependent on anaerobic glycolysis for energy production at the expense of increased intracellular lactat levels. To determine to which extent podocytes rely on mitochondrial respiration, we generated a podocyte specific electron transport chain mutant mouse line by mating a loxP-flanked mitochondrial transcription factor A (Tfam) allele with the podocin:cre transgene. We followed knockout and wildtype animals for a period of 12 months and assessed renal function and proteinuria. Interestingly, the mice did not develop a disease phenotype.


Accumulating evidence emphasizes the mitochondrial impact on podocyte function and the regulation of metabolic pathways. Within this 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 signalling events in states of health and disease. The long-term perspective of this project is to determine the mitochondrial contribution to podocyte-driven glomerular disease and potentially characterize novel, drugable signalling 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 in general.

Selected publications (CMMC-project related)

Schroeter CB, Koehler S, Kann M, Schermer B, Benzing T, Brinkkoetter PT, Rinschen MM (2018). Protein half-life determines expression of proteostatic networks in podocyte differentiation. FASEB J. 2018 Apr 25

Hagmann H, Mangold N, Rinschen MM, Koenig T, Kunzelmann K, Schermer B, BenzingT, Brinkkoetter PT (2018). Proline-dependent and basophilic kinases phosphorylate human TRPC6 at serine 14 to control channel activity through increased membraneexpression. FASEB J. 32(1):208-219. 

Koehler S, Brähler S, Braun F, Hagmann H, Rinschen MM, Späth MR, Höhne M, Wunderlich FT, Schermer B, Benzing T, Brinkkoetter PT (2017). Construction of a viral T2A-peptide based knock-in mouse model for enhanced Cre recombinase activity and fluorescent labeling of podocytes. Kidney Int. 91(6):1510-1517.

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

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 (2016). Prohibitin-2 Depletion Unravels Extra-Mitochondrial Functions at the Kidney Filtration Barrier. Am J Pathol. 186(5):1128-39.

Prof. Dr. Paul T Brinkkötter

Dept. II of Internal Medicine / RG location - CECAD Building

Prof. Dr. Paul T Brinkkötter

Principal Investigator C 5 / CAP 1

Work +49 221 478 89593

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

Publications - Paul T Brinkkötter

Link to PubMed

Group Members

Sebastian Brähler (PostDoc)
Henning Hagmann (PostDoc)
Sybille Köhler (PostDoc)
Cem Özel (PostDoc)
Mahsa Matin (PhD student)
Johanna Odenthal (PhD student)
Thomas Schömig (MD student)
Anja Klein (MD student)
Nicole Mangold (MD student)
Angelika Köser (technician)
Vivian Ludwig (MTA)

Figure 1

Additional loss of Oma1 fails to rescue podocyte specific Phb2-knockout mice.

Figure 2

Loss of Phb2 and/or Oma1 both lead to mTOR activation in glomerular podocytes as assessed by pS6 immunohistochemistry.

Figure 3

Podocyte function is independent of the mitochondrial OXPHOS machinery. Depicted are PAS stainings from 12-week old mice