Visual Universitätsmedizin Mainz

Evolutionary Biochemistry and Redox Medicine

Univ.-Prof. Dr. rer. nat. Bernd Moosmann

Our laboratory is interested in how evolutionary mechanisms have shaped today’s biochemistry in the animate nature and in humans. On a molecular level, evolution has sculptured all biochemical pathways including those that are related to human disease and aging. The elucidation of the causal factors that have moulded modern biochemistry might thus be of unique value for the understanding and treating of various human disorders. In this respect, our special focus is on neurodegenerative diseases (Niemann-Pick Disease and Alzheimer’s Disease), pathologies influenced by the mevalonate pathway (leading to cholesterol and selenoprotein synthesis), and the general biological aging process.

Our projects:

1. Oxidative and Usage-Dependent Neurodegeneration

Signs of oxidative stress and redox dysregulation are seen in a multitude of neurodegenerative disorders. However, there is an unsettled debate on whether these signs are in fact causally relevant originators of malfunction, or whether they rather reflect secondary signs of an already ongoing degenerative process. If aberrant oxidation indeed had a causal role in diseases like Alzheimer’s Disease, compounds modulating specific redox processes could be of substantial therapeutic value.

Towards the aim of a rational design of novel neuroprotective drugs, we are working on a systematic characterization of macromolecular damage in the young, old and diseased mammalian brain (in collaboration with Christian Behl, this Institute). In parallel lines of investigation, we are trying to clarify the potential role of usage-dependent processes as upstream triggers of age-related neurodegeneration. Translational aspects of this project are investigated in collaborations with Mathias Schreckenberger (Department of Nuclear Medicine) and with Kristin Engelhard and Christian Werner (Department of Anesthesiology).

  • Ohlow MJ, Moosmann B (2011). Phenothiazine: The seven lives of pharmacology’s first lead structure. Drug Discov. Today 16, 119-131.

  • Granold M, Moosmann B, Staib-Lasarzik I, Arendt T, del Rey A, Engelhard K, Behl C, Hajieva P (2015). High membrane protein oxidation in the human cerebral cortex. Redox Biol. 4, 200-207.

  • Hajieva P, Bayatti N, Granold M, Behl C, Moosmann B (2015). Membrane protein oxidation determines neuronal degeneration. J. Neurochem. 133, 352-367.

  • Sebastiani A, Granold M, Ditter A, Sebastiani P, Gölz C, Pöttker B, Luh C, Schaible EV, Radyushkin K, Timaru-Kast R, Werner C, Schäfer MK, Engelhard K, Moosmann B, Thal SC (2016). Posttraumatic propofol neurotoxicity is mediated via the proBDNF-p75NTR pathway in adult mice. Crit. Care Med. 44, e70-e82.

2. Evolutionary Proteomic Biochemistry

Proteine
Respiratory chain complexes of different animal species display similar overall structures (black). However, they do contain highly variable contents of redox-active amino acids such as methionine (red), as illustrated here on the example of cytochrome b from a feather star (left) and a stingless bee (right). The differential usage of redox-active amino acids in these proteins leads to a significantly different chemical stability towards oxidizing metabolites and free radicals.

Impressive amounts of molecular information on all forms of life have been collected by the DNA sequencing initiatives launched in the last two decades. Unfortunately, the functional interpretation of those data arrays is severely lagging behind all the sequencing efforts that continue to generate an increasingly complete genomic picture of life.

Employing comparative bioinformatics approaches on the proteome and genome level, we aspire to detect general rules of biochemical evolution that have shaped modern life during its billion-year history. Specifically, we are focussing on the evolution of the genetic code, the standard set of amino acids, the coenzymes, and the role of oxygen in the precipitation of these biochemical fundamentals. We believe that various formerly adaptive biochemical mechanisms might exist which in modern humans contribute to aging and disease.

  • Moosmann B, Behl C (2008). Mitochondrially encoded cysteine predicts animal lifespan. Aging Cell 7, 32-46.

    This story was featured by the political newsmagazine Focus

    The Aging Cell cover image highlighting our work

  • Bender A, Hajieva P, Moosmann B (2008). Adaptive antioxidant methionine accumulation in respiratory chain complexes explains the use of a deviant genetic code in mitochondria. Proc. Natl. Acad. Sci. USA 105, 16496-16501.

    The PNAS cover image highlighting our work

  • Schindeldecker M, Stark M, Behl C, Moosmann B (2011). Differential cysteine depletion in respiratory chain complexes enables the distinction of longevity from aerobicity. Mech. Ageing Dev. 132, 171-179.

  • Schindeldecker M, Moosmann B (2015). Protein-borne methionine residues as structural antioxidants in mitochondria. Amino Acids 47, 1421-1432.

  • Granold M, Hajieva P, Tosa M, Irimie FD, Moosmann B (2018). Modern diversification of the amino acid repertoire driven by oxygen. Proc. Natl. Acad. Sci. USA 115, 41-46.

3. Cholesterol, Selenoproteins and the Mevalonic Acid Pathway

Schema
The mevalonic acid pathway utilizes acetyl-CoA to assemble the majority of the body’s cholesterol. Concomitantly, it provides crucial intermediates for the synthesis of various other molecules that are indispensable for human health, such as ubiquinone (coenzyme Q10) and selenocysteine-tRNA. Statin-type cholesterol-lowering drugs inhibit the mevalonic acid pathway at an early step upstream of its branching points. In consequence, all products of the mevalonic acid pathway are influenced by these drugs, which might account for the many unexplained effects of statins in clinical practice.

Cholesterol-lowering drugs inhibiting the mevalonate pathway (statins) are among the most widely prescribed medicines world-wide. While their net beneficial effects in the secondary prevention of cardiovascular events have been convincingly demonstrated, there is a surprising lack of knowledge on the mechanisms that are in the end responsible for the observed benefit. Moreover, the mechanisms behind the apparent association of cholesterol with many other diseases beyond atherosclerosis have remained mysterious.

We hypothesize that a tissue-specific modulation of selenoprotein expression might be causal to both the clinical benefit of statins in atherosclerosis as well as their major side-effects such as myopathy. We are currently investigating this idea in different cellular and genetic model systems.

  • Kromer A, Moosmann B (2008). Statin-induced stalling of selenoprotein synthesis in hepatocytes. 37th American College of Clinical Pharmacology (ACCP) Annual Meeting 2008, Philadelphia, PA, USA. J. Clin. Pharmacol. 48, S1103.

    Andrea winning an abstract award at the 37th ACCP Meeting in Philadelphia

  • Kromer A, Moosmann B (2009). Statin-induced liver injury involves cross-talk between cholesterol and selenoprotein biosynthetic pathways. Mol. Pharmacol. 75, 1421-1429.

  • Fuhrmeister J, Tews M, Kromer A, Moosmann B (2012). Prooxidative toxicity and selenoprotein suppression by cerivastatin in muscle cells. Toxicol. Lett. 215, 219-227.