Mitochondrial DNA damage and repair in neurodegenerative disorders

Abstract

By producing ATP and regulating intracellular calcium levels, mitochondria are vital for the function and survival of neurons. Oxidative stress and damage to mitochondrial DNA during the aging process can impair mitochondrial energy metabolism and ion homeostasis in neurons, thereby rendering them vulnerable to degeneration. Mitochondrial abnormalities have been documented in all of the major neurodegenerative disorders-Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis. Mitochondrial DNA damage and dysfunction may be downstream of primary disease processes such as accumulation of pathogenic proteins. However, recent experimental evidence demonstrates that mitochondrial DNA damage responses play important roles in aging and in the pathogenesis of neurodegenerative diseases. Therapeutic interventions that target mitochondrial regulatory systems have been shown effective in cell culture and animal models, but their efficacy in humans remains to be established.

Figure 1

The pathogenic proteins of Alzheimer’ disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS) directly and/or indirectly cause mitochondrial dysfunction and apoptosis. Amyloid β-peptide (Aβ), a pathogenic protein in AD, can induce membrane lipid peroxidaton and the production of the toxic aldehyde 4-hydroxynonenal, resulting in perturbed cellular calcium homeostasis and energy metabolism. Aβ may accumulate in mitochondria and impair the function of electron transport enzymes. Pathogenic proteins of PD include α-synuclein, Parkin, DJ-1, and PTEN-induced putative kinas 1(PINK1) may indirectly promote mitochondrial DNA damage and dysfunction by impairing proteasome function and increasing ROS production. Aggregated α-synuclein increases oxidized lipids that may, in turn, disrupt membrane functions and increase neuronal vulnerability to excitotoxicity. Parkin associates with the mitochondrial outer membrane and may prevent release of cytochrome c, a neuroprotective function compromised by Parkin mutations. PINK1 is a mitochondrial kinase that may protect against oxidative stress-induced apoptosis. Mutant huntingtin (htt), with N-terminal polyglutamine repeats, directly interacts with mitochondrial membranes resulting in an altered mitochondrial Ca²⁺ retention and membrane depolarization. Decreased Ca²⁺ retention capacity increases the sensitivity of neurons to Ca²⁺-mediated excitotoxicity. Mutant htt may cause increased mitochondrial membrane permeability by binding to p53 and increasing the levels of nuclear p53 and p53 transcriptional activity, resulting in production of the pro-apoptotic protein Bax. Mutant Cu/Zn-superoxide dismutase (SOD1) which causes many cases of familial ALS, may directly damage mitochondria; aggregates of mutant SOD1 have been detected at the outer mitochondrial membrane and matrix, and mutant SOD1 may interact with Bcl-2 and compromise its cell survival-promoting function. Thus, in each of the major age-related neurodegenerative disorders pathogenic proteins may directly and/or directly damage mitochondrial DNA, alter mitochondrial membrane permeability and impair electron transport chain function. The damaged mitochondria may trigger apoptosis by releasing cytochrome c, the apoptosis-inducing factor (AIF) and Ca²⁺.