chapter  6
44 Pages

Mitochondrial DNA Mutation, Oxidative Stress, and Alteration of Gene Expression in Human Aging

Abstract................................................................................. 320 Introduction .......................................................................... 320 Mitochondrial OXPHOS Function Declines with Age....... 321 Mitochondrial DNA Mutations Accumulate with Age ...... 324 Aging-Associated Increase in Mitochondrial

ROS Production ........................................................... 327 Enhanced Oxidative Stress and Damage in

Aging Tissues............................................................... 330 DNA Repair Systems in Mitochondria............................... 333 Mitochondrial Role in Apoptosis during Aging.................. 335 Alterations in Gene Expression during Aging Process ..... 339 Concluding Remarks............................................................ 344 Acknowledgments................................................................. 346 References............................................................................. 346

ABSTRACT

A decline in respiratory function and increase in oxidative stress in mitochondria have been proposed as important contributors to human aging. A wide spectrum of alterations in mitochondria and mitochondrial DNA (mtDNA) has been observed in aged individuals and senescent cells. These include:

• Decline in mitochondrial respiratory function • Accumulation of mtDNA mutations • Alteration in the expression of the mitochondrial

genes • Increase in the rate of production of reactive oxygen

species (ROS) • Increase in the extent of oxidative damage to DNA,

proteins, and lipids

Responses to oxidative stress and their subsequent consequences in affected tissues play an important role in the deleterious effects of ROS on cellular function and on the apoptotic process, which culminate in aging and degenerative diseases. In this review, we focus on the roles that ROS play in aging-associated oxidative damage to mtDNA and proteins and on the oxidative stress responses of human cells at the molecular and cellular levels. The alterations of gene expression profiles elicited by oxidative stress in aging animals are discussed. Taking recent findings from this and other laboratories together, we suggest that the decline in respiratory function and increase in mitochondrial production of ROS and subsequent accumulation of mtDNA mutations and alteration in the expression of a few clusters of genes play an important role in the aging process.