tract, and never the other way around. The most likely explanation is that, as the daughter cells migrate away from the bile duct, some acquire additional somatic mtDNA mutations. This is consistent with "the streaming liver" hypothesis, where regenerating hepatocytes arise from a stem cell population in the canal of Hering and move outward into the liver parenchyma. 2 As previously observed, 1 the COX-deficient zones were morphologically normal, and in some healthy aged subjects, up to 5% of the liver showed a COX defect despite having normal biochemical indices of liver function. A strong selection bias, either for or against the mtDNA mutations, therefore seems unlikely. This is supported by our observation of clonally expanded synonymous mtDNA substitutions in regions with normal COX activity, which have presumably accumulated through random genetic drift. 3 The mtDNA mutations therefore appear to be a reliable marker of hepatocyte lineages.
The prevailing view is that mature hepatocytes divide every year, gradually replacing adjacent liver cells. On the other hand, stem cell activation is only thought to occur after an acute insult, or after chronic liver damage when the capacity for mature hepatocyte division has been overwhelmed. Our observations indicate that the stem cell population is active in healthy liver and contributes to hepatocyte turnover. Although we found no evidence that the mtDNA mutations compromise liver cell function, there is emerging evidence that stem cell proliferation could be compromised by somatic mtDNA mutations. If correct, then this could explain why the prognosis following acute liver insult is worse in older subjects. 4,5 Acknowledgment: We are very grateful to Dr. Simon Elliot and Mr.