Evidence for association of mitochondrial metabolism alteration with lipid accumulation in aging rats.

Adipogenesis and lipid accumulation during aging have a great impact on the aging process and the pathogenesis of chronic, age-related diseases. However, little is known about the age-related molecular changes in lipid accumulation and the mechanisms underlying them. Here, using 5-month- and 25-month-old rats (young and old, respectively), we found that epididymal fat is the only tissue to accumulate during aging. By testing tissues rich with mitochondria in old and young animals, we found that the old animals had elevated levels of triglycerides in their muscle, heart and liver tissues but not in their kidneys, while, the mRNA level of fatty acid synthase remained unchanged among the four tissues. Regarding lipid catabolism, we determined that the activities of mitochondrial ETC. complexes changed in aged rats (muscle: decreased complex I and V activities; heart: decreased complex I activity; liver: increased complex I and III activities; kidney: decreased complex I and increased complex II activities), while changes in mitochondrial content were not observed in the muscle, heart nor in the liver tissue except increased complex IV and V subunits in aged kidneys. Furthermore, decreased mitochondrial fusion marker Mfn2 and decreased PGC-1α level were observed in the aged muscle, heart and liver but remained unchanged in the kidneys. Down-regulation of Mfn2 with siRNA in 293T cells induced significant mitochondrial dysfunction including decreased oxygen consumption, decreased ATP production, and increased ROS production, followed by increased triglyceride content suggesting a contributing role of decreased mitochondrial fusion to lipid deposit. Meanwhile, judging from autophagy marker p62/SQSTM1 and LC3-II, autophagy was suppressed in the aged muscle, heart and liver but remained unchanged in the kidneys. Taken together, these data suggest that reduction in PGC-1α expression and disruption of mitochondrial dynamics and autophagy might contribute to lipid accumulation during aging.