Changes in neuronal CycD/Cdk4 activity affect aging, neurodegeneration, and oxidative stress

Aging Cell

Amalia Icreverzi¹  Aida Flor A. de la Cruz²  David W. Walker¹ 

[1] Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA;Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

关键词: aging;    mitochondria;    neurodegeneration;    oxidative stress;    superoxide;   

DOI  :  10.1111/acel.12376

来源: Wiley

【 摘 要 】

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 RNAi-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.

【 授权许可】

CC BY   
© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.