61 - Mitochondrial dynamics regulates metabolism during aging

Abstract

Cellular metabolism is intimately linked to mitochondrial functions. Mitochondrial dynamics is regulated by mitochondrial fission and fusion that influence the shape, size, and number of mitochondria. Dynamin-related guanosine triphosphatases regulate fission and fusion events: dynamin-related protein 1 (DRP1) regulates fission; mitofusin-1 and 2 (MFN1, MFN2) anchored in the outer mitochondrial membrane and optic atrophy 1 (OPA1) anchored in the inner mitochondrial membrane regulate fusion. Replicative and chronological lifespan are two different modes of cellular aging. Chronological lifespan (CLS) is defined as the duration during which quiescent normal cells retain their capacity to re-enter the proliferative cycle and then exit back to quiescence. This study investigates whether mitochondrial dynamics regulates metabolism during CLS . Results from bioenergetics measurements of quiescent primary cultures of normal human fibroblasts (NHFs) from subjects of different ages showed significant decreases in the glycolytic flux: 2-10 npH cell-1 s-1 in older (58-y, 61-y, 63-y, 68-y, and 70-y) compared to 12-16 npH cell-1 s-1 in younger (newborn, 3-d, 5-m, and 1-y) subjects. Surprisingly, mitochondrial respiration (oxygen consumption rate; OCR) increased significantly during CLS: 36-77 amol O2 cell-1 s-1 in older compared to 24-29 amol O2 cell-1 s-1 in younger subjects. The decrease in glycolytic flux and increase in OCR during CLS were also associated with a decrease in lactate and increase in ATP levels. Mitochondrial dynamics shifted more towards fusion during CLS. Genetic knock-down of MFN1 and OPA1 in old NHFs decreased OCR and enhanced glycolysis. These results support the hypothesis that mitochondrial dynamics regulates metabolic plasticity during aging; MFN1 and OPA1 regulate this process.