The chemotherapy drug cisplatin poisons the mitochondria in the inner ear, but why some patients lose their hearing while others do not remains unexplained. This project tests a new genetic explanation: mitonuclear interactions—where a fault in mitochondrial DNA only causes damage when paired with a specific fault in nuclear DNA. The researchers will use a specially bred mouse strain that carries such an interaction, exposing inner ear tissues and live mice to cisplatin. They will measure how mitochondrial metabolism, cell death, and hearing function change compared to normal mice. If mitonuclear interactions prove to be a key factor, the work could lead to genetic screening before chemotherapy. Doctors could then adjust cisplatin doses or offer protective treatments to patients whose genetic makeup puts them at higher risk of hearing loss. This is fundamental science—it does not test a therapy or a drug. But understanding why some ears are vulnerable is the first step toward personalised protection. The same genetic mechanism may also explain why hearing loss varies so widely after noise exposure or with ageing.
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Mitonuclear interactions (MI) occur when mutations in mitochondrial DNA produce a phenotype only in the presence of certain mutations in nuclear DNA. The chemotherapy drug cisplatin generates ototoxicity by compromising mitochondrial function, leading to loss of sensory hair cells, atrophy of the stria vascularis and loss of synaptic coupling. However, the high variability of incidence and severity in chemotherapy patients is poorly understood. We seek to understand whether and how MI contributes to the vulnerability of the inner ear to cisplatin ototoxicity by using the C57BL/6JMNX(FVB/NJ) mouse, a model of MI that exhibits subtle redox and respiratory defects. Firstly, we will evaluate the contribution of MI to the acute changes in mitochondrial metabolism, ROS generation and degeneration of tissue architecture in explant cultures of the postnatal mouse organ of Corti and stria vascularis. Secondly, we will examine in adult mice how MI affects hearing function following in vivo treatment with cisplatin, and the extent to which this correlates with mitochondrial dysfunction and changes in tissue architecture. Aside from providing the most comprehensive study of mammalian mitochondrial activity in the context of cisplatin ototoxicity to date, the results will increase understanding of the genetic factors underlying susceptibility to cisplatin ototoxicity and move towards personalised adjuvant treatments tailored to the variable genetic backgrounds of patients. This is the first study to investigate MI during ototoxicity, and will provide a basis for understanding the role of MI in other forms of hearing loss, including those induced by noise exposure and ageing.
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