Description

More than one-third of all enzymes found in eukaryotic cells are metalloproteins and require transition metals such as manganese (Mn) as redox-active cofactor for an array of biological reactions. Proteins that require Mn include mitochondrial superoxide dismutase, mannosyltransferases, phosphatases or glutamate synthetase. Yet, Mn can also compete with magnesium (Mg), thereby modulating the activity of DNA polymerases or metabolic regulators like TORC1. In some instances, Mn inhibits enzymatic activities linked to retrotransposition of DNA elements or telomere elongation. Overexposure to Mn leads to oxidative stress, disrupts cellular energy metabolism, promotes aggregation and exosomal cell-to-cell transmission of α-synuclein and is a source of pathological conditions underlying neurodegeneration in humans. Accordingly, Mn neurotoxicity has been implicated in neurodegenerative diseases such as Parkinson related Manganism or Alzheimer's disease. Interestingly, preliminary work of our group indicate that Mn toxicity may also be driven by light exposure. Although considered to be photobiologically safe, the blue-light fraction of ambient light affects the circadian rhythm and may cause retinal damage. Neurological diseases and age associated genome instability are a major challenge to human society. It is therefore important to improve our understanding on how an essential micronutrient like Mn drives disease states and on the mechanisms enabling to control Mn action to prevent human disease. Here, we propose the use of orthogonal approaches to improve our knowledge on the factors and mechanistic causes underlying Mn induced cell damage and disease. We will focus on evolutionary conserved protein functions involved in Mn homoeostasis to determine the factors and pathways involved in Mn driven cell death (manganatosis) using yeast and human cells as model systems.

Project investigators

• Helene Gaillard – Principal Investigator
• Ralf Erik Wellinger – Principal Investigator
• Rocío de los Angeles Domínguez Sierra
• Inés García De Oya

Funding entities

MICIU/AEI/10.13039/501100011033

FEDER, UE