Impairment of the proteasome is crucial for glucose-induced lifespan reduction in the mev-1 mutant of Caenorhabditis elegans.
Hyperglycemia is a hallmark of diabetes that is associated with diabetic complications and a reduction of lifespan. Using the mev-1 mutant of the nematode Caenorhabditis elegans we here tried to identify molecular mechanisms underlying the lifespan reducing effects of glucose. The lowest glucose concentration tested (10mM) caused a significant lifespan reduction at 37°C and was used to assess effects on mitochondrial efficiency, formation of protein carbonyls and levels of methylglyoxal, a precursor of advanced glycation end products (AGEs). RNA-interference (RNAi) served the identification of targets for glucose-induced damage. Levels of protein carbonyls and AGEs remained unaffected by 10mM glucose. Levels of reactive oxygen species inside mitochondria were increased but their scavenging by ascorbic acid did not influence lifespan reduction by glucose. Mitochondrial efficiency was reduced by glucose as concluded from a lowered P/O-ratio. A reduced lifespan of mev-1 that was unaffected by the addition of glucose resulted from RNAi of key players of mitochondrial unfolded protein response. Besides increased accumulation of misfolded proteins, reduced proteasomal degradation caused the same phenotype as was evidenced by RNAi for UBQ-1 or UBA-1. Accumulation of functionally impaired proteins, e.g. in mitochondria, underlies the lifespan reducing effects of glucose. Our study provides evidence for a crucial importance of the proteostasis network for lifespan regulation which is impaired by glucose.
Justus-Liebig-University of Giessen, Giessen, Germany.
Elena
E
Fitzenberger
Michael
M
Boll
Uwe
U
Wenzel
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D045303:Cytochromes b; D048909:Diabetes Complications / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D008136:Longevity / Q000235:genetics / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics*
D029742:Caenorhabditis elegans Proteins; C472666:MEV-1 protein, C elegans; D017382:Reactive Oxygen Species; D045303:Cytochromes b; D013385:Succinate Dehydrogenase; D046988:Proteasome Endopeptidase Complex; D005947:Glucose