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The Role of Complex I Assembly Factors during Prion Diseases: Insights into Mitochondrial Neurobiology

The Role of Complex I Assembly Factors during Prion Diseases: Insights into Mitochondrial Neurobiology

Objective

Mitochondria have a crucial role in cell survival and apoptosis, in particular in long-lived cells such as neurons. Mitochondria generate energetic potential through respiratory complexes I to IV, which constitute the electron transport chain. A number of studies demonstrates that mitochondrial integrity declines as a function of aging and dysfunctions may be exacerbated by age-related neurodegenerative diseases. Altered levels of complex I proteins have been found to be directly responsible for a decrease in energy production in Alzheimer’s and Parkinson's disease. Recently, a number of nuclear encoded mitochondrial proteins, denoted as “assembly factors” (AFs), have been identified as crucial components helping the complex I assembly. Defects in AFs (due to mutations or aberrant AFs processing) may cause complex I misassembly and mitochondrial dysfunctions leading to a broad spectrum of diseases, including neurological disorders in childhood-related dieseas as Leigh syndrome. The functional role of AFs during neurodegeneration has not been investigated yet. With the “Prion Respiration” project I propose to develop a research approach aimed at the identification of the biological role of three crucial complex I AFs (namely ECSIT, NDUFAF1 and ACAD9) in cellular and animal models using prion diseases as robust system to study neurodegenerative diseases. Subsequently, the role of prions in interfering the with the correct assembly of the AFs will be investigated using structural biology approaches, as SAXS and cryo-EM methods. The structural and functional characterization of key proteins involved in mitochondrial respiration will provide insights into the underlying mechanisms involved in neuronal function and may represent novel targets for structure-based drug design strategies to prevent or diminish the oxidative stresses underlying neurodegeneration.
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Coordinator

UNIVERSITA DEGLI STUDI DI TRENTO

Address

Via Calepina 14
38122 Trento

Italy

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 171 473,28

Project information

Grant agreement ID: 844194

Status

Grant agreement signed

  • Start date

    2 September 2019

  • End date

    1 September 2021

Funded under:

H2020-EU.1.3.2.

  • Overall budget:

    € 171 473,28

  • EU contribution

    € 171 473,28

Coordinated by:

UNIVERSITA DEGLI STUDI DI TRENTO

Italy