Caveolin3 Stabilizes McT1-Mediated Lactate/Proton Transport in Cardiomyocytes

2021 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​Caveolin3 Stabilizes McT1-Mediated Lactate/Proton Transport in Cardiomyocytes​
Peper, J.; Kownatzki-Danger, D.; Weninger, G.; Seibertz, F.; Pronto, J. R. D.; Sutanto, H. & Pacheu-Grau, D. et al.​ (2021) 
Circulation Research128(6).​ DOI: 

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Peper, Jonas; Kownatzki-Danger, Daniel; Weninger, Gunnar; Seibertz, Fitzwilliam; Pronto, Julius Ryan D.; Sutanto, Henry; Pacheu-Grau, David; Hindmarsh, Robin; Brandenburg, Sören ; Lehnart, Stephan E. 
Rationale: CAV3 (caveolin3) variants associated with arrhythmogenic cardiomyopathy and muscular dystrophy can disrupt post-Golgi surface trafficking. As CAV1 (caveolin1) was recently identified in cardiomyocytes, we hypothesize that conserved isoform-specific protein/protein interactions orchestrate unique cardiomyocyte microdomain functions. To analyze the CAV1 versus CAV3 interactome, we employed unbiased live-cell proximity proteomic, isoform-specific affinity, and complexome profiling mass spectrometry techniques. We demonstrate the physiological relevance and loss-of-function mechanism of a novel CAV3 interactor in gene-edited human induced pluripotent stem cell cardiomyocytes. Objective: To identify differential CAV1 versus CAV3 protein interactions and to define the molecular basis of cardiac CAV3 loss-of-function. Methods and Results: Combining stable isotope labeling with proximity proteomics, we applied mass spectrometry to screen for putative CAV3 interactors in living cardiomyocytes. Isoform-specific affinity proteomic and co-immunoprecipitation experiments confirmed the monocarboxylate transporter McT1 (monocarboxylate transporter type 1) versus aquaporin1, respectively, as CAV3 or CAV1 specific interactors in cardiomyocytes. Superresolution stimulated emission depletion microscopy showed distinct CAV1 versus CAV3 cluster distributions in cardiomyocyte transverse tubules. CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9 nuclease)-mediated CAV3 knockout uncovered a stabilizing role for McT1 surface expression, proton-coupled lactate shuttling, increased late Na + currents, and early afterdepolarizations in human induced pluripotent stem cell-derived cardiomyocytes. Complexome profiling confirmed that McT1 and the Na,K-ATPase form labile protein assemblies with the multimeric CAV3 complex. Conclusions: Combining the strengths of proximity and affinity proteomics, we identified isoform-specific CAV1 versus CAV3 binding partners in cardiomyocytes. McT1 represents a novel class of metabolically relevant CAV3-specific interactors close to mitochondria in cardiomyocyte transverse tubules. CAV3 knockout uncovered a previously unknown role for functional stabilization of McT1 in the surface membrane of human cardiomyocytes. Strikingly, CAV3 deficient cardiomyocytes exhibit action potential prolongation and instability, reproducing human reentry arrhythmias in silico. Given that lactate is a major substrate for stress adaption both in the healthy and the diseased human heart, future studies of conserved McT1/CAV3 interactions may provide rationales to target this muscle-specific assembly function therapeutically.
Issue Date
Circulation Research 
EXC 2067: Multiscale Bioimaging 
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz 
SFB 1002 | A06: Molekulare Grundlagen mitochondrialer Kardiomyopathien 
SFB 1002 | A09: Lokale molekulare Nanodomänen-Regulation der kardialen Ryanodin-Rezeptor-Funktion 
SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur 
SFB 1002 | D02: Neue Mechanismen der genomischen Instabilität bei Herzinsuffizienz 
SFB 1002 | S01: In vivo und in vitro Krankheitsmodelle 
SFB 1002 | S02: Hochauflösende Fluoreszenzmikroskopie und integrative Datenanalyse 
SFB 1002 | A13: Bedeutung einer gestörten zytosolischen Calciumpufferung bei der atrialen Arrhythmogenese bei Patienten mit Herzinsuffizienz (HF) 
SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente 
Working Group
RG Hasenfuß 
RG Lehnart 
RG Rehling (Mitochondrial Protein Biogenesis) 
RG Voigt (Molecular Pharmacology) 
RG Brandenburg 
RG Cyganek (Stem Cell Unit) 
RG Lenz 
RG Wollnik 
RG Urlaub (Bioanalytische Massenspektrometrie) 
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