Biology of aging and neurodegenerative diseases: the mitochondrial theory.

BOVERIS, A.; VALDEZ, L.; LORES ARNAIZ, S.; ALVAREZ, S. ; COSTA. L.E.

Vancouver

Congreso; 17th World Congress of the International Association of Gerontology; 2001

International Association of Gerontology

The concept that mitochondria are involved in aging derives from the views of Gerschman et al. (1954) and Harman (1956) linking senescence to the injurious effect of the free radicals produced in the univalent reduction of oxgyen in cells and tissues. This hypothesis is more attractive when applied to mitochondria than to cells and tissues after considering that: (a) mitochondria are the most important subcellular site of free radical production, especially considering O2- and NO; (b) O2- steady state concentration in the mitochondrial matrix is about 5 to 10 times higher than in the cytosolic and nuclear spaces; (c) mtDNA is in close proximity to the sites of generation of the hydroxyl radical and peroxynitrite and is not protected by histones; (d) accumulation of faulty synthetized proteins might compromise energy transduction; and (e)dysfunctional mitochondria signal for lysosomal digestion and for apoptosis. During the last few years, experimental evidence has indicated that mitochondria evolve during aging to a state of oxidative stress and dysfunctionality. Mitochondrial aging by oxyradical and peroxynitrite induced damage occurs through mtDNA damage and relatively specific protein inactivation, such as adenine nucleotide translocase. This process leads to a state of dysfunctional mitochondria, which are not able to keep membrane potential and ATP synthesis. Dysfunctional mitochondria release O2-, Ca2+ and cytochrome c to the cytosol and signal for organelle digestion by primary lysosomes when the number of dysfunctional mitochondria in the cell is relatively small, or, for apoptosis , when the number of dysfunctional mitochondria in the cell is relatively large.