Open AccessChanges in neuronal CycD/Cdk4 activity affect aging, neurodegeneration, and oxidative stress
Author(s) -
Icreverzi Amalia,
Cruz Aida Flor A.,
Walker David W.,
Edgar Bruce A.
Publication year - 2015
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12376
Subject(s) - neurodegeneration , biology , microbiology and biotechnology , oxidative stress , mitochondrial biogenesis , mitochondrion , reactive oxygen species , cyclin dependent kinase 5 , tfam , dnaja3 , kinase , protein kinase a , mitochondrial dna , genetics , cyclin dependent kinase 2 , biochemistry , mitochondrial fusion , gene , medicine , disease
Summary Mitochondrial dysfunction has been implicated in human diseases, including cancer, and proposed to accelerate aging. The Drosophila Cyclin‐dependent protein kinase complex cyclin D/cyclin‐dependent kinase 4 (CycD/Cdk4) promotes cellular growth by stimulating mitochondrial biogenesis. Here, we examine the neurodegenerative and aging consequences of altering CycD/Cdk4 function in Drosophila . We show that pan‐neuronal loss or gain of CycD/Cdk4 increases mitochondrial superoxide, oxidative stress markers, and neurodegeneration and decreases lifespan. We find that RNA i‐mediated depletion of the mitochondrial transcription factor, Tfam, can abrogate CycD/Cdk4's detrimental effects on both lifespan and neurodegeneration. This indicates that CycD/Cdk4's pathological consequences are mediated through altered mitochondrial function and a concomitant increase in reactive oxygen species. In support of this, we demonstrate that CycD/Cdk4 activity levels in the brain affect the expression of a set of ‘oxidative stress’ genes. Our results indicate that the precise regulation of neuronal CycD/Cdk4 activity is important to limit mitochondrial reactive oxygen species production and prevent neurodegeneration.