333-LB: Impact of Aging on Mitochondrial Respiratory Chain Expression and Pancreatic Islet Cell Composition by Using a Mitochondrial DNA Mutator Mouse Model

Introduction: Age-related cumulative mitochondrial mutations can cause mitochondrial dysfunction. The mitochondrial DNA mutator mouse (PolgA^mut/mut) is a model of premature ageing and has been previously shown to develop impaired insulin secretion with age.

Methods: Immunofluorescence was used to study mitochondrial respiratory chain protein expression (complex I and IV) and the cell composition in islets. Experiments were conducted on pancreas tissue from PolgA^mut/mut mice and age-matched wild type (WT) mice at two ages: 12 weeks (young) and 44 weeks (old).

Results: (1) Comparing young WT mice versus old WT mice, there was no difference in islet complex I expression, while islet size and beta cell number increased with age (both P<0.01). (2) Comparing young PolgA ^mut/mut mice versus young WT mice, complex I expression was significantly lower (P<0.01) in islets from young PolgA ^mut/mut mice. However, there were no significant differences in islet size and cell composition between young PolgA ^mut/mut and young WT mice. (3) Comparing old PolgA ^mut/mut mice versus old WT mice, complex I expression was significantly lower (P<0.01) and complex IV expression was significantly higher (P<0.01) in islets from the old PolgA ^mut/mut mice. Old PolgA ^mut/mut islets had a lower beta cell percentage (mean ± SEM; 71.8 ± 4 % vs. 89.3 ± 4% P<0.01) but a higher alpha cell percentage (mean ± SEM; 29.6 ± 4 % vs. 12.5 ± 5%; P<0.01) versus old WT mice (both P<0.01).

Conclusions: In PolgA ^mut/mut mice, complex I deficiency was already present in the islets of young mice and persisted with age. This was associated with a proportional increase in alpha cells and decrease in beta cells in islets from old PolgA ^mut/mut versus the old WT mice. We conclude that complex I deficiency in PolgA ^mut/mut mice is linked to altered islet cell composition with increasing age.