Fine-Tuning of Drp1/Fis1 Availability by AKAP121/Siah2 Regulates Mitochondrial Adaptation to Hypoxia

Abstract

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.

Local cAMP signaling in disease at a glance

“…Components of the cAMP signaling cascade are also coordinated to regulate this process (see Cardiovascular disease panel). AKAP121 (also known as AKAP1) enables PKAmediated phosphorylation of dynaminrelated protein 1 (DRP1), which prevents it from associating with the fission factor FIS1 on the mitochondrial membrane (Kim et al, 2011). Hypoxia results in the increased expression and activity of the ubiquitin ligase SIAH2, which then ubiquitylates AKAP121, leading to its breakdown and consequent dephosphorylation of DRP1.…”

“…Hypoxia results in the increased expression and activity of the ubiquitin ligase SIAH2, which then ubiquitylates AKAP121, leading to its breakdown and consequent dephosphorylation of DRP1. Upon its dephosphorylation, DRP1 is able to interact with FIS1 to trigger mitochondrial fission and apoptosis (Kim et al, 2011). Intriguingly, another AKAP, mAKAP, binds to the transcription factor hypoxia-inducible factor 1a (Wong et al, 2008).…”

Novel Function of E3 Ubiquitin Ligase Siah2 to Regulate ROS Metabolism

“…In addition, the knockdown of Siah2, but not Keap1, was shown to significantly attenuate the hypoglycemia-mediated reduction of Nrf2 expression [40] . Mitochondria are critical for cell survival, and their morphology is associated with susceptibility to cell death signals [41] . In ischemiainduced cardiomyocyte cell death, Siah2 regulates the availability of the mitochondrial scaffolding protein AKAP121 and subsequent mitochondrial dynamics.…”

Regulation of Mitochondrial Dynamics and Cell Fate

“…Notably, Kim et al demonstrated that AKAP121 was ubiquitinated and subsequently degraded in a manner dependent upon SIAH2. 42 Hence, regulation of AKAP121 by SIAH2 is a key nodal point in Drp1 activation and mitochondrial fission. Further, mice germ-lines deleted for SIAH2 had smaller infarcts and reduced incidence of cell death, which highlights the importance of the SIAH2-AKAP121 axis in the regulation of Drp1 and mitochondrial fission.…”

“…Further, mice germ-lines deleted for SIAH2 had smaller infarcts and reduced incidence of cell death, which highlights the importance of the SIAH2-AKAP121 axis in the regulation of Drp1 and mitochondrial fission. 42 Regulation of Drp1 by Mitotic Kinases Aurora A and Cyclin B-CDK1 Coordinated fission and fusion of mitochondria is a critical step in normal cell division and proliferation. A recent study by Kashatus et al 29 provided new insight into the regulation of mitochondrial fission events during cell division.…”