Human mtDNA sublimons resemble rearranged mitochondrial genoms found in pathological states

Sublimons, originally identified in plant mitochondria, are defined as rear ranged mtDNA molecules present at very low levels. We have analysed the pri mary structures of sublimons found in human cells and tissues and estimated their abundance. Each tissue of a given individual contains a wide range o f different sublimons and the most abundant species differ between tissues in a substantially systematic manner, Sublimons are undetectable in rho (0) cells, indicating that they are bona fide derivatives of mtDNA, They are m ost prominent in postmitotic tissue subject to oxidative stress. Rearrangem ent break-points, often defined by short direct repeats, sire scattered, bu t hotspot regions are clearly identifiable, notably near the end of the D-l oop, The region between the replication origins is therefore frequently eli minated, One other hotspot region is located adjacent to a known site of pr otein binding, suggesting that recombination may be facilitated by protein- protein interactions. For a given primary rearrangement, both deleted and p artially duplicated species can be detected. Although each sublimon is typi cally present at a low level, at most a few copies per cell, sublimon abund ance in a given tissue can vary over three orders of magnitude between heal thy individuals. Collectively, therefore, they can represent a non-negligib le fraction of total mtDNA, Their structures are very similar to those of t he rearranged molecules found in pathological states, such as adPEO and MNG IE; therefore, we propose that, as in plants, human mtDNA sublimons represe nt a pool of variant molecules that can become amplified under pathological conditions, thus contributing to cellular dysfunction.