Mitochondrial membrane potential in aging cells.

Decreased mitochondrial membrane potential (DeltaPsi(M)) has been found in a variety of aging cell types from several mammalian species. The physiological significance and mechanisms of the decreased DeltaPsi(M) in aging are not well understood. This review considers the generation of DeltaPsi(M) and its role in ATP generation together with factors that modify DeltaPsi(M) with emphasis on mitochondrial membrane permeability, particularly the role of a multiprotein membrane megapore, the mitochondrial permeability transition pore complex (PTPC). Previous data showing decreased DeltaPsi(M) in aged cells is considered in relation to the methods available to estimate DeltaPsi(M). In the past the majority of studies used whole cell rhodamine 123 fluorescence to estimate DeltaPsi(M) in lymphocytes from mice or rats. Imaging of DeltaPsi(M) in living, in situ mitochondria using laser confocal scanning microscopy offers advantages over whole cell measurements or those from isolated mitochondria, particularly if several different potentiometric dyes are employed. Furthermore, high resolution imaging of the newer fixable potentiometric dyes allows immunocytochemistry for specific proteins and DeltaPsi(M) to be examined in the same cells or even the same mitochondria. We found that decreased DeltaPsi(M) in p53 overexpression-induced or naturally occurring senescence is associated with decreased responsiveness of the PTPC to agents that induce either its opening or closing. The decreased PTPC responsiveness seems to reflect, at least in part, decreased levels of a key PTPC protein, the adenine nucleotide translocase. We also consider the possible basis for decreased DeltaPsi(M) in fibroblasts from patients with Parkinson's disease, an age-related neurodegenerative disease. Finally, we speculate on the mechanisms and functional significance of decreased DeltaPsi(M) in aging.