Drosophila simulans as a novel model for studying mitochondrial metabolism and aging

Mitochondria generate much of the cellular energy through the process of oxidative phosphorylation (OXPHOS). OXPHOS function may be affected by a mutation in any of the mitochondrial (mt) DNA encoded genes and/or nuclear encoded genes that produce proteins imported into the mitochondrion that form (or assemble) the five complexes located on the inner mitochondrial membrane. Decreasing mitochondrial OXPHOS efficiency, defined as the amount of inorganic phosphate incorporated into ATP per mole of oxygen consumed (ADP:O ratio), results in an increase in the production of reactive oxygen species (ROS). ROS damages mtDNA, cell membranes, and lipids and, according to the free radical theory of aging, the rate of its accumulation is a major factor affecting lifespan. In humans, studies of age-specific cohorts suggest that extended longevity is associated with specific mtDNA types (mitotypes). However, the influence of each mitotype appears to be dependent on the nuclear genetic background in which it resides. These association studies are intuitively appealing, but since the age groups are necessarily from different cohorts there is no rigorous means of eliminating spurious associations due to accidents of sampling or environment. The critical need is to determine the extent to which (i) mitochondrial encoded genes, (ii) nuclear encoded genes whose products are imported into the mitochondrion, and (iii) interactions among mtDNA and nuclear (mitonuclear) encoded proteins, influence mitochondrial metabolism and life history traits including survival. This need can be efficiently accomplished in the fly Drosophila simulans owing to its (i) high mtDNA diversity, (ii) ease of genetic and experimental manipulations, (iii) sequence of multiple complete genomes, (iv) short generation time, (v) ease of collection and (vi) ability to raise large numbers so that sex and age-specific effects can be determined. The utility of the fly model is supported by the conservation of the OXPHOS pathway and the mitochondrial genome in humans, mice and Drosophila.