Partnership Opportunities

Understanding Neurodegeneration in Mitochondrial Diseases

Using Ndufs4 mouse models to understand mTOR activation in Leigh Syndrome and other mitochondrial diseases

Technology Overview

Mitochondrial diseases are highly varied, arising from mutations in hundreds of genes, and can lead to cellular damage in affected tissues. One of the most common forms of mitochondrial disease is Leigh Syndrome (LS), a progressive neurodegenerative disorder that is characterized by developmental delay, movement disorders, and ultimately death. Progressive lesions in the brainstem and cerebellum are the hallmarks of the encephalopathy. Most patients with LS exhibit symptoms as infants, and die within a year of diagnosis, as there is no cure. The poor prognosis for this disease drives scientists to search for underlying pathways that might allow interventions to be introduced.

Margaret SedenskyDr. Margaret SedenskyPhil MorganDr. Philip Morgan

One field of work conducted by Drs. Sedensky and Morgan involves the use of a novel mouse model of LS to understand disease progression and potential therapeutic targets. This mouse model of LS, in which a complex I subunit, NDUFS4, is knocked out, recapitulates symptoms seen in human patients diagnosed with mutations in Ndufs4, as well as other LS-associated mutations. Significant findings have included varying levels of brain abnormality in different regions, presenting an unprecedented opportunity to understand the mechanisms by which complex I dysfunction produces region-specific progressive neurodegeneration.

Work by Drs. Sedensky and Morgan has shown that mitochondrial function in LS cases is localized to specific CNS regions, leaving many regions of the brain unaffected. Electrophysiologic studies have shown an increase in synaptic excitatory signaling in the hippocampus of the Ndufs4(KO) mouse. In addition, restriction of the mutation to glutamatergic cell specific expression recapitulates the pattern of the total KO, while GABAergic and cholinergic expression do not. Work by this group has also shown that treatment of Ndufs4 with rapamycin alleviates CNS damage in a manner consistent with metabolic effects rather than inflammatory pathways. The rapamycin target (mTOR) is known to rescue glutamate toxicity.

While rapamycin is not advised for sustained use, and is even more risky when used in pediatric patients, the ability to reduce CNS damage by mTOR suppression is a valuable step in developing long-term treatment options for LS patients. Moving forward, Drs. Sedensky and Morgan are interested in understanding cellular changes due to dysfunction of Ndufs4, and identifying additional targets that can help restore function. 

Stage of Development

  • Pre-clinical in vivo

Partnering Opportunities

  • Collaborative research opportunity
  • Sponsored research agreement
  • Consultation agreement


  1. Johnson SC, Kayser EB, Bornstein R, Stokes J, Bitto A, Park KY…Sedensky MM, Morgan PG. Regional metabolic signatures in the Ndufs4(KO) mouse brain implicate defective glutamate/α-ketoglutarate metabolism in mitochondrial disease. Mol Genet Metab. 2020;130(2):118-132.
  2. Dancy B, Brockway N, Ramadasan-Nair R, Yang Y, Sedensky M, Morgan PGlutathione S-transferase mediates an ageing response to mitochondrial dysfunctionMechanisms of Ageing and Development. 2016;153:14-21.
  3. Morgan P, Higdon R, Kolker N, Bauman A, Ilkayeva O, Newgard C, Kolker E, Steele L, Sedensky MComparison of proteomic and metabolomic profiles of mutants of the mitochondrial respiratory chain in Caenorhabditis elegansMitochondrion. 2015;20:95-102.
  4. Johnson S, Yanos M, Kayser E, Quintana A, Sangesland M, Castanza A, Uhde L, Hui J, Wall V, Gagnidze A, Oh K, Wasko B, Ramos F, Palmiter R, Rabinovitch P, Morgan P, Sedensky M, Kaeberlein M. mTOR Inhibition Alleviates Mitochondrial Disease in a Mouse Model of Leigh SyndromeScience. 2013;342(6165):1524-1528.
  5. Quintana A, Morgan P, Kruse S, Palmiter R, Sedensky M. Altered Anesthetic Sensitivity of Mice Lacking Ndufs4, a Subunit of Mitochondrial Complex IPLoS ONE. 2012;7(8):e42904.

Learn More

    To learn more about partnering with Seattle Children’s Research Institute on this or other projects, email the Office of Science-Industry Partnerships