Abstract
Leigh syndrome is a severe neurodegenerative disease caused by mutations affecting mitochondrial electron transport chain function, the most common of which impair complex I. Children with Leigh syndrome acquire symptoms of psychomotor regression, ataxia, failure to thrive, seizures, and typically die by the age of 3. There are no treatments for Leigh syndrome and disease pathophysiology is poorly understood. Recently, mitochondria transfer has been described as a method to provide metabolic support to cells with impaired respiratory function. However, the application of mitochondria transfer-based therapies to improve mitochondrial disease has not been explored. Here, I show that bone marrow transplant improves morbidity and mortality in the Ndufs4 KO mouse model of Leigh syndrome and led to widespread transfer of donor mitochondria to Ndufs4 KO acceptor cells. These findings were recapitulated via administration of isolated mouse mitochondria to Leigh syndrome mice, establishing novel therapeutic approaches leveraging mitochondria transfer for the treatment of mitochondrial diseases. I show that these therapies are associated with no change to immune cell composition or inflammatory cytokine production, suggesting healthy mitochondria are intrinsically non- immunogenic. I further explore the effect of complex I deficiency on mitochondrial function using multiplexed quantum sensing for the first time in mouse primary cells. Measurement of intracellular temperature revealed decreased temperature in Ndufs4 KO cells, which was improved by mitochondria transplant. Further, I show that mitochondria coordinate cellular temperature and magnetism in a manner dependent on complex I function. Finally, I provide preliminary evidence that this process is dysregulated in cells from patients with Leigh syndrome, suggesting this disease can be characterized as a thermomagnetic disorder. This work reveals potential new approaches for the treatment of Leigh syndrome and suggests that thermomagnetic regulation could be a novel therapeutic target for this disease.
Committee Chair
Jonathan Brestoff
Committee Members
Gregory Wu; Joel Schilling; Natalie Niemi; Shankar Mukherji
Degree
Doctor of Philosophy (PhD)
Author's Department
Biology & Biomedical Sciences (Immunology)
Document Type
Dissertation
Date of Award
12-31-2025
Language
English (en)
DOI
https://doi.org/10.7936/tgqf-kp89
Author's ORCID
0000-0002-4671-7088
Recommended Citation
Varnum, Stella, "Mitochondria Transfer-based Therapy for the Mitochondrial Disease Leigh Syndrome" (2025). Arts & Sciences Theses and Dissertations. 3694.
The definitive version is available at https://doi.org/10.7936/tgqf-kp89