Cyclic AMP-dependent Protein Kinase Phosphorylation of Drp1 Regulates Its GTPase Activity and Mitochondrial Morphology*

By Chuang-Rung Chang, C. Blackstone. Journal of Biological Chemistry, 2007

770 citations recorded by the source corpus.

Mitochondria in cells comprise a tubulovesicular reticulum shaped by dynamic fission and fusion events. The multimeric dynamin-like GTPase Drp1 is a critical protein mediating mitochondrial division. It harbors multiple motifs including GTP-binding, middle, and GTPase effector (GED) domains that are important for both intramolecular and intermolecular interactions. As for other members of the dynamin superfamily, such interactions are critical for assembly of higher-order structures and cooperative increases in GTPase activity. Although the functions of Drp1 in cells have been extensively studied, mechanisms underlying its regulation remain less clear. Here, we have identified cAMP-dependent protein kinase-dependent phosphorylation of Drp1 within the GED domain at Ser637 that inhibits Drp1 GTPase activity. Mechanistically, this change in GTPase activity likely derives from decreased interaction of GTP-binding/middle domains with the GED domain since the phosphomimetic S637D mutation impairs this intramolecular interaction but not Drp1-Drp1 intermolecular interactions. Using the phosphomimetic S637D substitution, we also demonstrate that mitochondrial fission is prominently inhibited in cells. Thus, protein phosphorylation at Ser637 results in clear alterations in Drp1 function and mitochondrial morphology that are likely involved in dynamic regulation of mitochondrial division in cells.

Subfields: Clinical Biochemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2e7565fc9da79f767a7fc6c548d5f1584a6e1cdb

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Citations in the corpus

During autophagy mitochondria elongate, are spared from degradation and sustain cell viability (2011, background): “Conversely, phosphorylation of Ser 637 by PKA promotes mitochondrial elongatio”
Metabolic regulation of mitochondrial dynamics (2016, background): “, forskolin), β-adrenergic stimulation, or forced exercise (Fig. 3; Chang and Blackstone, 2007; Cribbs and Strack, 2007).”
Mitochondrial dynamics in mammalian health and disease. (2009, background): “To date, the cellular processes reported to modulate DRP1 activity, or vice versa, are apoptosis, neuronal function, cardiac and muscle differentiation, cell cycle, the second-messenger molecule cAMP through protein kinase A (PKA) and calcium, the latter through CaMKI and the phosphatase calcineurin”
The novel tail-anchored membrane protein Mff controls mitochondrial and peroxisomal fission in mammalian cells. (2008, background): “, 2007) and inactivated by cAMPdependent protein kinase (PKA) in quiescent cells (Chang and Blackstone, 2007; Cribbs and Strack, 2007).”
MiD49 and MiD51, new components of the mitochondrial fission machinery (2011, background): “Similarly, GFP–Drp1S600D, which shows decreased GTPase activity and mitochondrial recruitment (Chang & Blackstone, 2007), was also found at mitochondria following MiD51 expression (Fig 4C).”
Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle (2011, methodology): “Drp1-K38A (9) or a control plasmid (pCDNA3) using the Neon transfec-”
Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria (2008, neutral): “GTPase activity of recombinant Drp1 is greatly inhibited by PKA, yet the activity of Drp1 carrying the phosphomimetic S637D mutation is only slightly reduced (10).”
Mechanisms of mitochondrial fission and fusion. (2013, background): “These sites include Ser616, which is phosphorylated by protein kinase C (PKC) d, Rock kinase, CDK1/ Cyclin B or CAMK-Ia (Taguchi et al. 2007; Han et al. 2008; Qi et al. 2011; Wang et al. 2012), and Ser637, which is phosphorylated by protein kinase A (PKA) (Chang and Blackstone 2007; Cribbs and Strac”
The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. (2012, positive): “The phosphorylation by cyclic AMP-dependent kinase (PKA) at serine 637 site of human Drp-1 inhibits its GTPase activity and prevents mitochondrial fission (Chang and Blackstone, 2007; Cribbs and Strack, 2007).”
Mitochondrial dynamics in health and disease: mechanisms and potential targets (2023, background): “kinases regulating phosphorylation at the Ser637, acts in a cAMPdependent manner which is indirectly responsive to high and low changes in cAMP/ATP.(76,77) In a similar manner, activation of AMPK or restrain of mammalian target of rapamycin (mTOR) is demonstrated to induce mitochondrial fusion durin”