Autosomal dominant optic atrophy (ADOA) and Leber's hereditary optic neuropathy (LHON) are the two most common inherited optic neuropathies, they are each caused by deficiencies of mitochondrial function, and result in death of Retinal Ganglion Cells (RGCs), causing blindness. Thus RGCs are especially sensitive to deficits of mitochondrial function for an unknown reason. Our overarching goal is to elucidate the mito-pathophysiological mechanism of these mitochondrial optic neuropathies, and develop therapeutic leads. Currently no curative therapy exists for ADOA and LHON for multiple reasons. The reasons include the lack of an RGC-specific pathophysiological mechanism for the disease, the lack of animal models, and the lack of a high-throughput screening assay for drugs that improve mitochondrial function. We have addressed each of these issues in the former grant period and request support to continue our studies. For example, we have demonstrated that mitochondrial complex 1 inhibition signals cell death through the activation of a 'mitoinjury response': mito comp1AE ROSAEERAE ATF4AE targetsAE death, and this mitoinjury response and cell death can be blocked by blocked by interruption of the signal at ER or ATF4. We observe that persistent activation of this response by mitochondrial oxidative stress results in cellular dysfunction and death, and that inhibition of this response rescues cells from death. In animal models of the diseases, LHON: the ndufs4 mouse, and ADOA: the opa1 mouse, there is neurodegeneration of RGCs, and dendropathy of RGCs, respectively, resulting in defects of visual function. Thus, our plan has three overarching goals. First, to elucidate the pathophysiological mechanism of RGC death in two recently-derived animal models of mitochondrial disease. Secondly, we will investigate specific aspects of signaling in cellular models of the diseases. Thirdly, we will screen libraries to isolate drugs that rescue mitochondrial function and block ROS and cell death, and test them in the animal models, in preparation for clinical trials in humans.

Public Health Relevance

LHON and ADOA are the two most common inherited optic neuropathies. Our project is to validate a specific pathophysiological mechanism we have developed from our previous award in two animal models of LHON and ADOA, the ndufs4 and opa1 mouse. In addition we carry out a 'repurposing'drug screening isolate drugs that increase mitochondrial function, and will test these in cell and animal models of LHON and ADOA.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Chin, Hemin R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Veterinary Sciences
Schools of Veterinary Medicine
United States
Zip Code
Sahdeo, Sunil; Tomilov, Alexey; Komachi, Kelly et al. (2014) High-throughput screening of FDA-approved drugs using oxygen biosensor plates reveals secondary mitofunctional effects. Mitochondrion 17:116-25
Shan, Yuxi; Cortopassi, Gino (2012) HSC20 interacts with frataxin and is involved in iron-sulfur cluster biogenesis and iron homeostasis. Hum Mol Genet 21:1457-69
Tomilov, Alexey A; Ramsey, Jon J; Hagopian, Kevork et al. (2011) The Shc locus regulates insulin signaling and adiposity in mammals. Aging Cell 10:55-65
Schoenfeld, Robert; Wong, Alice; Silva, Jillian et al. (2010) Oligodendroglial differentiation induces mitochondrial genes and inhibition of mitochondrial function represses oligodendroglial differentiation. Mitochondrion 10:143-50
Tomilov, Alexey A; Bicocca, Vincent; Schoenfeld, Robert A et al. (2010) Decreased superoxide production in macrophages of long-lived p66Shc knock-out mice. J Biol Chem 285:1153-65
Rolo, Anabela P; Palmeira, Carlos M; Cortopassi, Gino A (2009) Biosensor plates detect mitochondrial physiological regulators and mutations in vivo. Anal Biochem 385:176-8
Silva, Jillian M; Wong, Alice; Carelli, Valerio et al. (2009) Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia. Neurobiol Dis 34:357-65
Lu, Chunye; Schoenfeld, Robert; Shan, Yuxi et al. (2009) Frataxin deficiency induces Schwann cell inflammation and death. Biochim Biophys Acta 1792:1052-61
Napoli, Eleonora; Morin, Dexter; Bernhardt, Rita et al. (2007) Hemin rescues adrenodoxin, heme a and cytochrome oxidase activity in frataxin-deficient oligodendroglioma cells. Biochim Biophys Acta 1772:773-80
Prigione, Alessandro; Cortopassi, Gino (2007) Mitochondrial DNA deletions induce the adenosine monophosphate-activated protein kinase energy stress pathway and result in decreased secretion of some proteins. Aging Cell 6:619-30

Showing the most recent 10 out of 23 publications