Research Projects

Mitochondrial defects play a critical role in early and late-onset childhood ataxia and adult neurometabolic diseases affecting multiple organs, with a high rate of 1 in 5000 prevalence worldwide. One of the major challenges in mitochondrial disorders is the extreme clinical heterogeneity affecting multiple organs due to the ubiquitous nature of the mitochondrial function and dual genetic control of the oxidative phosphorylation (OXPHOS) system. In addition to the 37 genes encoded by the mitochondrial genome, there are more than 1500 genes encoded by the nuclear genome that play a critical role in mitochondrial DNA maintenance, OXPHOS, mitochondrial biogenesis, replication, transcription, and post-transcriptional modifications, mitochondrial DNA repair, and metabolic pathways. Intriguingly, mitochondrial DNA (mtDNA) is more vulnerable to oxidative damage due to its proximity to the electron transport chain and lack of protective histones. Unlike nuclear DNA, mitochondria are not supported by robust DNA repair machinery. Notably, mtDNA damage impairs mitochondrial function, which is linked with pathological phenotypes impacting the brain and cognition. We have previously shown mitochondrial dysfunction is connected to neurodegenerative disorders due to mutations in critical DNA repair genes like TDP1, and TFAM-mitochondrial transcription factor. Utilising whole-exome analysis in clinically characterised hereditary spastic paraplegia and mitochondrial encephalopathy patients, we identified mutations in ZFYVE26, TRNT1, DGUOK, and SUCLG2, which are involved in mtDNA maintenance. However, little is known regarding DNA repair defects and mitochondrial encephalopathy directly in patients. The current proposal aims to identify the mitochondrial disorder in an Indian patient cohort by comprehensive clinical evaluation, utilise genome-wide screening of clinically established mitochondrial disorder patients to identify novel nuclear gene mutations associated with mitochondrial dysfunction, and directly establish patient-derived iPSCs to discover the intrinsic biological function of the identified mutations. Finally, for mechanistic insight into the disease, we will investigate the role of dysfunctional nuclear-mitochondrial crosstalk in contributing to primary mitochondrial disorders using CRISPR-edited neuronal cell lines. The crosstalk between mitochondrial dysfunction and nuclear DNA repair defects will provide new insight into better disease management and therapy for mitochondrial diseases.