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Ann N Y Acad Sci. 1998 Nov 20;854:128-54.

Mitochondrial DNA mutations and age.

Author information

1
Department of Biomedical Chemistry, Faculty of Medicine, University of Nagoya, Japan. ozawa@med.nagoya-u.ac.jp

Abstract

Apopotic cell death is reported to be prominent in the stable tissues of the failing heart, in cardiomyopathies (CM), in the sinus node of complete heart block, in B cells of diabetes mellitus, and in neurodegenerative diseases. Recently, mitochondrial (mt) control of nuclear apoptosis was demonstrated in the cell-free system. The mt bioenergetic crisis induced by exogenously added factors such as respiratory inhibitors leads to the collapse of mt transmembrane potential, to the opening of the inner membrane pore, to the release of the apoptotic protease activating factors into cytosol, and subsequently to nuclear DNA fragmentation. However, the endogenous factor for the mt bioenegertic crisis in naturally occurring cell death under the physiological conditions without vascular involvement has remained unknown. Recently devised, the total detection system for deletion demonstrates the extreme fragmentation of mtDNA in the cardiac myocytes of senescence, and mt CM harboring maternally inherited point mutations in mtDNA and on the cultured cell line with or without mtDNA disclosed that mtDNA is unexpectedly fragile to hydroxyl radial damage and hence to oxygen stress. The great majority of wild-type mtDNA fragmented into over two hundreds types of deleted mtDNA related to oxidative damage, resulting in pleioplasmic defects in the mt energy transducing system. The mtDNA fragmentation to this level is demonstrated in cardiac myocytes of normal subjects over age 80, of an mtCM patient who died at age 20 and one who died at age 19, of a recipient of heart transplantation at age 7 with severe mtCM, and in mtDNA of a cultured cell line under hyperbaric oxygen stress for two days, leading a majority of cells to apoptotic death on the third day. The extreme fragility of mtDNA could be the missing link in the apoptosis cascade that is the physiological basis of aging and geriatrics of such stable tissues as nerve and muscle.

[Indexed for MEDLINE]

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