New insights into structure and function of mitochondria and their role in aging and disease.

摘要

This review covers some novel findings on mitochondrial biochemistry and discusses diseases due to mitochondrial DNA mutations as a model of the changes occurring during physiological aging. The random collision model of organization of the mitochondrial respiratory chain has been recently challenged on the basis of findings of supramolecular organization of respiratory chain complexes. The source of superoxide in Complex I is discussed on the basis of laboratory experiments using a series of specific inhibitors and is presumably iron sulfur center N2. Maternally inherited diseases due to mutations of structural genes in mitochondrial DNA are surveyed as a model of alterations mimicking those occurring during normal aging. The molecular defects in senescence are surveyed on the basis of the "Mitochondrial Theory of Aging", establishing mitochondrial DNA somatic mutations, caused by accumulation of oxygen radical damage, to be at the basis of cellular senescence. Mitochondrial production of reactive oxygen species increases with aging and mitochondrial DNA mutations and deletions accumulate and may be responsible for oxidative phosphorylation defects. Evidence is presented favoring the mitochondrial theory, with primary mitochondrial alterations, although the problem is made more complex by changes in the cross-talk between nuclear and mitochondrial DNA.