PhD Studentship: Fuel, Iron, and Fire Mitochondrial Iron Metabolism in Ageing

Project Outline

Skeletal muscle undergoes progressive loss of mass and function during ageing, a process termed sarcopenia. This decline arises from reduced myogenesis and degeneration of existing fibres, leading to frailty and an increase in metabolic disease. The hallmarks of ageing propose that ageing is driven by the decline of mitochondrial function and accumulation of oxidative damage. Mitochondria act as metabolic hubs, hosting the oxidative phosphorylation and iron–sulfur cluster (Fe–Sc) biogenesis. Fe–Sc are essential cofactors for respiration, DNA maintenance and redox homeostasis. Their synthesis requires cysteine as a sulphur donor, linking mitochondrial iron and thiol handling to antioxidant systems. Disruption of Fe–S biogenesis leads to iron misregulation, impaired respiration and excess oxidation. One outcome of disturbed iron–thiol metabolism is vulnerability to ferroptosis, a cell death driven by iron-dependent lipid peroxidation[1]. Ferroptotic susceptibility depends on iron and sulfite handling as well as lipid composition and selenoprotein peroxidases. Thus, dietary factors such as selenium intake and lipids, together with mitochondrial Fe–S cluster assembly, may act as upstream regulators of ferroptosis sensitivity in ageing muscle.

When mitochondria decline, protective stress responses are activated. The oxidative stress response mediated by Nrf2 can upregulate cysteine and Fe metabolism and antioxidant defences. Previous work has shown that these pathways mitigate ferroptosis in mitochondrial cardiomyopathy[2]. This project will investigate how mitochondrial Fe–S metabolism and cysteine handling intersect with ferroptosis in ageing muscle.

Objectives

1. Characterise mitochondrial Fe–S biogenesis and cysteine metabolism in aged myoblasts
2. Determine ferroptosis sensitivity in aged myoblasts and test the influence of selenium and lipids
3. Evaluate Nrf2 activation and ferroptosis in aged mouse skeletal muscle

Funding notes:

This is a PhD studentship with the Midlands Integrated Biosciences Training Partnership, funded by BBSRC and in partnership with the University of Warwick, Aston University, Harper Adams University, Coventry University, and the University of Leicester. For more details please visit: https://warwick.ac.uk/fac/cross_fac/mibtp/ or https://www.birmingham.ac.uk/about/college-of-life-and-environmental-sciences/midlands-integrative-biosciences-training-partnership

How to apply:

To apply, please follow this link, make an account, and submit an application via the university online admissions portal (via the above ‘Apply’ button). This link is unique to the MIBTP programme; please do not use any other link to apply to this project or your application may be rejected: https://sits.bham.ac.uk/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=FR607G&code2=000576

References:

1. Ahola et al. Trends in Cell Biology 2024 doi: 10.1016/j.tcb.2023.06.002.
2. Ahola et al. Cell Metabolism 2022 DOI: 10.1016/j.cmet.2022.08.017

Advert information