Several mtDNA lineages have recently been associated with increased longevity and decreased propensity, for Alzheimer Disease (AD) and Parkinson Disease (PD). Mutations that define these lineges change highly conserved amino acids and occurred at key positions that modulated the coupling efficiency of oxidative phosphorylation (OXPHOS). As a consequence, the mitochondrial electron transport chain is more depleted of electrons.This reduces both mitochondrial reactive oxygen species (ROS) production and cellular oxidative stress. The end result is the preservation of cell, tissue,and organ function from degeneration and thus aging. The goal of the current proposal is to analyze the physiological consequences of these mutations in humans by correlating mtDNA haplogroups with functional differences in mitochondria of cultured somatic cells.This will be tested through 1) the development of transmitochondrial cybrids containing identical nuclear backgrounds but mitochondria from different lineages, 2) the characterization of OXPHOS enzyme activities and coupling,ROS production and mtPTP sensitivity of these cell lines and 3) examination of gene expression profiles for each cell line to identify differentially expressed genes arising from haplotype specific differences.
| Poole, Jason C; Procaccio, Vincent; Brandon, Martin C et al. (2010) Multiplex analysis of mitochondrial DNA pathogenic and polymorphic sequence variants. Biol Chem 391:1115-30 |
| Hendrickson, Sher L; Kingsley, Lawrence A; Ruiz-Pesini, Eduardo et al. (2009) Mitochondrial DNA haplogroups influence lipoatrophy after highly active antiretroviral therapy. J Acquir Immune Defic Syndr 51:111-6 |
| Hendrickson, Sher L; Hutcheson, Holli B; Ruiz-Pesini, Eduardo et al. (2008) Mitochondrial DNA haplogroups influence AIDS progression. AIDS 22:2429-39 |
