Journal article
Fine-Tuning of Drp1/Fis1 Availability by AKAP121/Siah2 Regulates Mitochondrial Adaptation to Hypoxia
H Kim, MC Scimia, D Wilkinson, RD Trelles, MR Wood, D Bowtell, A Dillin, M Mercola, ZA Ronai
Molecular Cell | CELL PRESS | Published : 2011
Abstract
Defining the mechanisms underlying the control of mitochondrial fusion and fission is critical to understanding cellular adaptation to diverse physiological conditions. Here we demonstrate that hypoxia induces fission of mitochondrial membranes, dependent on availability of the mitochondrial scaffolding protein AKAP121. AKAP121 controls mitochondria dynamics through PKA-dependent inhibitory phosphorylation of Drp1 and PKA-independent inhibition of Drp1-Fis1 interaction. Reduced availability of AKAP121 by the ubiquitin ligase Siah2 relieves Drp1 inhibition by PKA and increases its interaction with Fis1, resulting in mitochondrial fission. High AKAP121 levels, seen in cells lacking Siah2, atte..
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Awarded by National Heart, Lung, and Blood Institute
Funding Acknowledgements
We thank Drs. Peter Ratcliffe (University of Oxford, UK), Craig Blackstone (National Institute of Neurological Disorders and Stroke [NINDS], National Institutes of Health [NIH]), David Chan (Caltech), and Olexander Korchynsky (University of Amsterdam) for generous gifts of DNA constructs and antibodies; Randall Johnson (University of California, San Diego) for HIF1 alpha MEFs, and Ed Monosov (Sanford-Burnham Medical Research Institute) for assistance with electron microscopy. We thank members of the Ronai lab for discussions and Dr. Susan Taylor for critical comments. This work was supported by National Cancel Institute (NCI) grants CA1111515 and CA128814 (to Z.A.R.) and by National Heart, Lung, and Blood Institute (NHLBI) grants HL088266 and HL098053 and California Institute for Regenerative Medicine RC1-00132-1 (to M.M.). M.C.S. is a California Institute for Regenerative Medicine (CIRM) clinical fellow.