Mitochondria play essential roles in various critical biological processes, including the production of ATP, regulation of intracellular calcium homeostasis, and production of reactive oxygen species. Mitochondria contain their own DNA (mtDNA), and each mitochondrion contains multiple copies of mtDNA. We are interested in understanding how local mtDNA variations contribute to the initiation and progression of neurodegenerative diseases and developing therapeutic strategies for the diseases. We focus on primary mitochondria genetic diseases, including Leber’s Hereditary Optic Neuropathy (LHON), Maternally Inherited Leigh Syndrome (MILS), Neurogenic Ataxia and Retinitis Pigmentosa (NARP), and Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS). Using a novel mitochondrial targeting system invented by former Lab leader, the late Dr. John Guy, we successfully delivered wild-type alleles into the organelle and rescued impaired respiration functions in cybrids homoplasmic for mitochondrial gene mutations. We also used this strategy to introduce the mutant human mitochondrial gene into mouse zygotes and generated a bona fide transgenic mitochondrial mouse model. Meanwhile, collaborating with Dr. Vittorio Porciatti and Dr. Byron Lam, we perform pre-clinical studies for the treatment of LHON patients with a confirmed mutated ND4 gene using the mitochondrial targeting technology to deliver wild-type alleles directly into mitochondria. We will test the safety of this therapy and its effectiveness in preventing and restoring visual loss in LHON animal models relative to normal controls.
