Mitochondrial membrane potential in aging cells

Decreased mitochondrial membrane potential (Δπ_M) has been found in a variety of aging cell types from several mammalian species. The physiological significance and mechanisms of the decreased Δπ_Min aging are not well understood. This review considers the generation of Δπ_Mand its role in ATP generation together with factors that modify Δπ_Mwith emphasis on mitochondrial membrane permeability, particularly the role of a multiprotein membrane megapore, the mitochondrial permeability transition pore complex (PTPC). Previous data showing decreased Δπ_Min aged cells is considered in relation to the methods available to estimate Δπ_M. In the past the majority of studies used whole cell rhodamine 123 fluorescence to estimate Δπ_Min lymphocytes from mice or rats. Imaging of Δπ_Min 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 Δπ_Mto be examined in the same cells or even the same mitochondria. We found that decreased Δπ_Min 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 Δπ_Min fibroblasts from patients with Parkinsons disease, an age-related neurodegenerative disease. Finally, we speculate on the mechanisms and functional significance of decreased Δπ_Min aging.