CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 27739424.
- Also identified by DOI 10.1038/ncomms13189 and PMC identifier 5067512.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Mitochondrial permeability transition pore (mPTP) is involved in cardiac dysfunction during chronic β-adrenergic receptor (β-AR) stimulation. The mechanism by which chronic β-AR stimulation leads to mPTP openings is elusive. Here, we show that chronic administration of isoproterenol (ISO) persistently increases the frequency of mPTP openings followed by mitochondrial damage and cardiac dysfunction. Mechanistically, this effect is mediated by phosphorylation of mitochondrial fission protein, dynamin-related protein 1 (Drp1), by Ca<sup>2+</sup>/calmodulin-dependent kinase II (CaMKII) at a serine 616 (S616) site. Mutating this phosphorylation site or inhibiting Drp1 activity blocks CaMKII- or ISO-induced mPTP opening and myocyte death in vitro and rescues heart hypertrophy in vivo. In human failing hearts, Drp1 phosphorylation at S616 is increased. These results uncover a pathway downstream of chronic β-AR stimulation that links CaMKII, Drp1 and mPTP to bridge cytosolic stress signal with mitochondrial dysfunction in the heart.
Medical subject headings
- Calcium-Calmodulin-Dependent Protein Kinase Type 2
- Dynamins
- Isoproterenol
- Mitochondrial Membrane Transport Proteins
- Myocytes, Cardiac
- Receptors, Adrenergic, beta