Aging and mitochondrial genome

Mitochondrial DNA (mtDNA) carries the information for 13 of the 60 polypeptides of mitochondrial respiratory complexes; together with nuclear DNA (nDNA) it is responsible for their biogenesis. Aging is a complex phenomenon mainly associated with loss of mitochondrial bioenergetic capacity. Therefore, it was advanced that the degenerative processes of senescence could be caused by defects of mtDNA (1, 2). We used the rat to study the role of the mitochondrialgenetic system in aging. In aged rat brain and heart we found a reduced steady-state level of mt transcripts (3) due to reduced RNA synthesis (4), an unchanged mitochondrial DNA copy number per cell (5), a reduced number of mtDNA molecules harboring the triplex strand structure in the "D-Ioop region" (6), a low but increasing age-related content of mtDNA molecules harboring a 4.8 K bases deletion (7), and an increasing number of mtDNA deletions with aging (8). We also found that the reduced steady-state level of mt transcripts is reversible; indeed, 1-hour of acetyl-L-camitine (AC) pre-treatment of senescent rats was able to bring back the level of mt transcripts to the value of adult rats (3), and the effect was timeand dose-dependent (9). Recently, we reported that mitochondrial protein synthesis is also reduced in aging rat (8). Reduced mitochondrial protein synthesis could not be due only to reduced transcription, because mitochondrial transcripts are present in excess in the cell. We therefore propose that reduced transcription and translation in aged rat mitochondria are, at least in part, a consequence of the age-clependentdecline of the bioenergetic state of mitochondria (10), caused by the alteration in mitochondrial membrane composition and in the transport of some metabolites (11). Our recently obtained results in human skeletal muscle (12) seem to confirm this possibility.