Fine-tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia

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 scaffol...

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Published in:Molecular cell Vol. 44; no. 4; p. 532
Main Authors: Kim, Hyungsoo, Scimia, Maria C, Wilkinson, Deepti, Trelles, Ramon D, Wood, Malcolm R, Bowtell, David, Dillin, Andrew, Mercola, Mark, Ronai, Ze'ev A
Format: Journal Article
Language:English
Published: United States 18.11.2011
Subjects:
A Kinase Anchor Proteins - genetics
A Kinase Anchor Proteins - metabolism
Adaptation, Physiological
Animals
Apoptosis
Caenorhabditis elegans
Caenorhabditis elegans Proteins - genetics
Caenorhabditis elegans Proteins - metabolism
Cell Line
Dynamins - genetics
Dynamins - metabolism
Humans
Hypoxia - genetics
Hypoxia - metabolism
Hypoxia - pathology
Immunohistochemistry
Lentivirus
Longevity
Membrane Fusion
Mice
Mice, Transgenic
Mitochondria - physiology
Mitochondrial Membranes - metabolism
Mitochondrial Proteins - genetics
Mitochondrial Proteins - metabolism
Myocardial Ischemia - genetics
Myocardial Ischemia - metabolism
Myocardial Ischemia - pathology
Myocytes, Cardiac - cytology
Myocytes, Cardiac - metabolism
Phosphorylation
Transduction, Genetic
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
ISSN:1097-4164, 1097-4164
Online Access:Get more information
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Summary: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, attenuate fission and reduce apoptosis of cardiomyocytes under simulated ischemia. Infarct size and degree of cell death were reduced in Siah2(-/-) mice subjected to myocardial infarction. Inhibition of Siah2 or Drp1 in hatching C. elegans reduces their life span. Through modulating Fis1/Drp1 complex availability, our studies identify Siah2 as a key regulator of hypoxia-induced mitochondrial fission and its physiological significance in ischemic injury and nematode life span.
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ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2011.08.045