This is a Fellowship Grant awarded to Dr James O’Sullivan at King’s College London, in 2025.
Background
Hearing loss affects millions worldwide, often as a side effect of life-saving treatments like chemotherapy.
Cisplatin, a common chemotherapy drug, can damage the cell’s mitochondria, which are structures responsible for producing energy.
Within the structures of the inner ear, this damage accumulates and causes cell death, leading to irreversible hearing loss. However, not everyone experiences the same level of damage, and understanding how differences in our genes might explain this variability could help address cisplatin-induced hearing loss.
One type of genetic variation is the interaction between the DNA in mitochondria (mtDNA) and the DNA in the cell’s nucleus (nuDNA). (The nucleus is the cellular structure that houses the genome i.e. the majority of our DNA and genes).
Throughout the history of life on earth, mtDNA and nuDNA have evolved together to “match up”. However, occasionally it is possible to inherit mtDNA that is “mismatched” to the nuDNA, which can result in increased vulnerability to disease.
These mismatches are termed mitonuclear interactions. Because mitonuclear interactions affect how mitochondria function, they could therefore influence how susceptible we are to cisplatin-induced hearing loss.
Aims
To explore this, James will use mitochondrial exchange (MNX) mice, which are specifically engineered to have mismatched nuDNA and mtDNA.
Previous work has showed that these mice have subtle differences in mitochondrial metabolism that predispose them to a variety of diseases, although any effects on hearing haven’t been pursued in detail.
By studying the structure and function of the inner ear of MNX mice compared to normal mice, James aims to uncover how mitonuclear interactions affect the inner ear’s response to cisplatin.
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Benefit
By understanding how mitonuclear interactions influence susceptibility to cisplatin, James hopes to make progress towards personalised treatments that minimise hearing loss after chemotherapy.
Furthermore, the research will shed light on the broader role of mitonuclear interactions in inner ear function. These interactions may also be relevant in the study of hearing loss caused by other factors such as noise exposure and ageing.