Schilling 2017 J Mol Cell Cardiol
|Loss of caveolin-1 alters cardiac mitochondrial function and increases susceptibility to stress.|
Event: J Mol Cell Cardiol
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Caveolae, membrane microdomains enriched in cholesterol, glycosphingolipids, sphingomyelin and the protein caveolin, are critical to ischemic tolerance. We have previously described a specific role for caveolin-3 (Cav-3) in cardiac protection via regulation of mitochondrial function; however, little is known about the role of caveolin-1 (Cav-1) in cardiac mitochondrial bioenergetics. We hypothesized that Cav-1 is crucial in maintaining healthy cardiac mitochondria.
We performed a series of experiments to assess the role of Cav-1 uponmitochondrial functionality, comparing heart tissues and isolated mitochondria from wildtype (WT) and global Cav-1 knock-out (KO)mice. Percoll-purifiedWT mitochondria were immunogold labeled and imaged by TEMto localize Cav-1 protein to specific mitochondrial membranes. Furthermore, oxygen consumption was evaluated in isolated papillary muscle fibers by high-resolution respirometry using Oroboros O2k oxygraph. Superoxide free radical productionwas investigated by electron paramagnetic resonance imaging (EPR) using the spin probe DEPMPO in isolated mitochondria.
Immunogold labeling showed Cav-1 localization to outer and inner mitochondrial membranes. In Cav-1 KO mice relative oxygen flux was slightly increased in the presence of complex I substrates and ADP. Furthermore, in Cav-1 KO mice, cytochrome c response (a marker for outer mitochondrial damage) was significantly correlated to total complex I & II respiration (malate, pyruvate, glutamate, ADP, and succinate) with increased respiration at higher cytochrome c responses, indicating potential outer mitochondrial membrane damage. ROS was decreased in Cav-1 KO mice during state IV respiration with complex I & II substrates measured by EPR suggesting overall decreased mitochondrial function.
Cav-1 may be a critical regulator of cardiac mitochondrial function. Cav-1 may therefore be a viable therapeutic target to alter cardiac mitochondrial bioenergetics.
Labels: MiParea: Respiration, Genetic knockout;overexpression, mt-Medicine, Pharmacology;toxicology Pathology: Cardiovascular
Organism: Mouse Tissue;cell: Heart Preparation: Isolated mitochondria
Coupling state: OXPHOS Pathway: N, CIV, NS HRR: Oxygraph-2k
- Univ California
- VA San Diego Healthcare System; San Diego, CA, USA