Structural Bioenergetics
Proton pumping NADH:ubiquinone oxidoreductase (complex I) is a 1 MDa membrane protein complex with a key function for efficient energy production of the cell. Complex I utilizes the redox energy released in the electron transfer reaction from NADH to ubiquinone to pump protons across the inner mitochondrial membrane or the cell membrane of bacteria. Redox-linked proton translocation by complex I contributes considerably to the electrochemical proton gradient that ultimately drives ATP synthesis in oxidative phosphorylation. A variety of neuromuscular and neurodegenerative human diseases have been linked with complex I dysfunction. However, the molecular details of energy conversion by complex I are still controversial and we are just beginning to understand how this intricate molecular machine is assembled.
We use the aerobic yeast Yarrowia lipolytica as a model organism to study mitochondrial complex I. We have determined the high-resolution cryoEM structure of the enzyme complex in an ongoing collaboration with the MPI Biophysics, Frankfurt. Recently, we have determined the structures of complex I assembly intermediates, one of which is associated with the transacylase tafazzin. Tafazzin is involved in the remodeling of cardiolipin (CL), the signature lipid of mitochondria. Due to its unique structure and physicochemical properties, CL induces negative membrane curvature and is thought to play a critical role for establishing mitochondrial cristae morphology. Mutations in the tafazzin gene cause Barth syndrome, a rare life-threatening multi-system disorder. Our goal is to understand complex I biogenesis and the transacylation mechanism of tafazzin at the molecular level.
Complex I is the best-known member of a superfamily of membrane proteins that has evolved by the combination of membrane-bound redox proteins with a special type of multi-subunit cation/proton antiporter. In collaboration with the MPI of Biophysics, we have determined the structure of a bacterial Mrp type Na+/H+ antiporter and investigate the molecular details of a histidine switch mechanism that operates in the antiporter and in complex I. Our biochemical and structural work is complemented by molecular simulations in collaboration with the University of Helsinki and the MPI of Biophysics.
The Structural Bioenergetics Group is part of CRC1507 and the SCALE excellence cluster and is also funded by DFG project ZI552/7-1.
High-resolution cryo-EM structure of complex I from Yarrowia lipolytica.
Prof. Dr. Volker Zickermann
Anton Altmeyer
Anton was born in Dresden but grew up near Wiesbaden. He studied chemistry at the Johannes Gutenberg-Universität Mainz and obtained his diploma degree in 2016. He went on to add a master degree in biophysics from the Goethe University of Frankfurt. Since 2021 he is a Ph.D. student in the Structural Bioenergetics Group with the goal to unravel the mysteries of Mrp-type sodium/ proton antiporters.
Dr. Jonathan Schiller
Jonathan studied biology at the University of Regensburg, where he received his master’s degree in 2019. In his master’s thesis, he investigated the evolution of Rab and SPIRE protein interactions in actin-mediated vesicle transport. In 2020, he started his PhD project in the Structural Bioenergetics Group and focused on the structural characterization of complex I assembly intermediates. As a Postdoctoral Researcher he now works on the mechanism of the transacylase tafazzin, a key enzyme in mitochondrial lipid metabolism.
Katharina Friedrich
Katharina obtained her bachelor’s degree in biochemistry at the Goethe University of Frankfurt in 2023. She went on to study biochemistry in her master’s and is currently working on her thesis investigating the role of different assembly factors of the respiratory chain.
Monalisa Sarkar
Monalisa obtained her BS-MS dual degree from the Indian Institute of Science Education and Research Kolkata in 2023 with a major in chemical sciences and a minor in biological sciences. In 2023, she started her PhD in the Structural Bioenergetics Group where she is working on the structural characterization of Complex I assembly intermediates and assembly factors. Monalisa is affiliated with the MPI of Biophysics (joint project P14 in CRC1507, Vonck/Zickermann).
Neele Manik
Neele Manik studied pharmacy at the Goethe University Frankfurt, where she received her license as a pharmacist in 2024. During her practical year she focused on target engagement in living cells. In July 2025 she started her PhD in the Structural Bioenergetics Group, where she works on the structural characterization of complex I assembly intermediates.
Past Members:
With a molecular mass of almost 1 MDa mitochondrial NADH:ubiquinone oxidoreductase (complex I) is the largest membrane protein complex of the respiratory chain. We have determined the structure of complex I from the aerobic yeast Yarrowia lipolytica by X-ray crystallography and cryo-EM. A number of unresolved issues call for structural characterization of different functional states of the enzyme complex. We combine a wide spectrum of structural and functional studies to unravel the molecular mechanism of redox-linked proton translocation by complex I.
In the high-resolution structure of complex I, a chain of protein bound water molecules (red spheres) extends along the central hydrophilic axis of the membrane arm. The inset shows a detailed view on subunit ND2 with a putative proton transfer pathway to the matrix side.
The assembly of complex I is an intricate process involving at least 20 assembly factors to ensure the correct association of more than 40 subunits, the insertion of cofactors and the post-translational modification of several polypeptides. The assembly pathway has been extensively characterized but the structural basis of complex I biogenesis and the molecular details of assembly factor function are largely unknown. We achieved the first high-resolution structural characterization of an assembly intermediate. The structure offered clues on the function of assembly factor NDUFAF2. Recently, we succeeded in isolating assembly intermediates of the proximal proton pump module. Their cryo-EM structures offered new insight into the function of assembly factors and revealed a link of complex I assembly with cardiolipin remodeling.
CryoEM structures of the early and late assembly intermediates of the proximal proton pump module of complex I.
Cardiolipin (CL) is the signature phospholipid of mitochondria. Compared to other phospholipids, the unusual size ratio between the hydrophobic moiety with four acyl chains and the rather small hydrophilic head group is remarkable. Due to its unique structure and physicochemical properties, CL induces negative membrane curvature and is thought to play a critical role for establishing mitochondrial cristae morphology. CL is synthesized in the inner mitochondrial membrane, followed by an obligatory remodeling process that is catalysed by the transacylase tafazzin. Tafazzin has a broad substrate spectrum and transfers fatty acids from phospholipids to lysophospholipids, e.g. monolyso cardiolipin (MLCL). It is remarkable that in contrast to other acyltransferases, tafazzin does not use acyl-adducts of coenzyme A (CoA) or an acyl carrier protein (ACP). In humans, mutations in the tafazzin gene cause Barth syndrome, a rare hereditary disease. The characteristic symptoms are cardiomyopathy, skeletal myopathy, neutropenia and growth retardation. We have determined the structure of tafazzin and our goal is to unravel the yet unknown mechanism of transacylation.
Cardiolipin is thought to be critical for establishing cristae morphology (left). Remodelling of cardiolipin is catalysed by the transacylase tafazzin (right).
Mrp-type antiporters represent a unique subgroup among cation proton antiporters. In contrast to antiporters of other families, these multi-subunit membrane protein complexes comprise spatially separated pathways for protons and sodium, suggesting a long-range coupling mechanism. Several subunits of Mrp-type antiporter have orthologs in proton or sodium pumping complexes of the complex I superfamily. Our structure of the Bacillus pseudofirmus complex revealed a previously unknown mobile region in the terminal subunit MrpA. Here, in the proton translocating domain of the complex, a histidine residue moves between three separate proton paths like a switch. Our goal is to elucidate the mechanism of sodium/proton antiport in molecular detail and how it relates to the mechanism of respiratory complex I.
A “Histidine Switch” operates in Mrp antiporters and in complex I.