Investigating the Role of FIS1 in Regulating Mitochondria-Lysosome Contact Sites under Hypoxia

University of Sheffield
School of Biosciences

Applications accepted all year round
Self-Funded PhD Students Only

About the Project

Mitochondria-lysosome contact sites (MLCSs) are dynamic inter-organelle interfaces crucial for cellular homeostasis, facilitating metabolic exchange, organelle quality control and adaptive stress responses. Under hypoxic conditions, when oxygen levels are low, cells undergo significant mitochondrial remodelling. This includes increased formation of MLCSs and the emergence of megamitochondria engulfing lysosomes (MMEL), a process implicated in mitochondrial self-digestion and hypoxia adaptation. However, the molecular regulators of MLCS dynamics during hypoxia are poorly understood.

FIS1 (Fission 1 protein) is a mitochondrial outer membrane protein best known for its role in mitochondrial division and mitophagy regulation. Recent studies reveal that FIS1, together with Mid51, also orchestrates MLCS dynamics by recruiting Rab7-GAPs (e.g., TBC1D15) to mitochondria, thereby promoting Rab7 inactivation and lysosome untethering. Loss of FIS1 disrupts this process, leading to abnormal lysosomal anchoring and impaired organelle organization. Despite these insights, the specific role of FIS1 in regulating MLCSs under hypoxia and facilitating cellular adaptation remains unclear.

This project hypothesises that FIS1 regulates MLCS dynamics during hypoxia to coordinate mitochondrial remodelling, lysosomal reorganisation and cell survival. Three aims will be pursued using live/Fixed-cell imaging and biochemical assays: (1) characterise MLCS dynamics and the role of FIS1 under hypoxia; (2) determine how FIS1 affects mitochondrial morphology, MMEL, and protein degradation; and (3) assess the impact of FIS1-dependent MLCS regulation on lysosomal trafficking, mitochondrial quality control and hypoxia-induced cell death.

Please apply for this project using this link: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying

By uncovering how FIS1 modulates MLCSs during hypoxic stress, this study will advance our understanding of organelle crosstalk and cellular resilience. Findings may also identify novel therapeutic targets for diseased conditions involving mitochondrial dysfunction and hypoxia, such as neurodegeneration, ischaemia and cancer.

For more information about the project, or to discuss a potential application, please contact Dr Chun Guo (c.guo@sheffield.ac.uk)

Funding Notes

First class or upper second 2(i) in a relevant subject. To formally apply for a PhD, you must complete the University's application form using the following link:

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All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information.