We show here that the apposition of plasma membrane caveolae and mitochondria (first noted in electron micrographs >50 yr ago) and caveolae-mitochondria interaction regulates adaptation to cellular stress by modulating the structure and function of mitochondria. In C57Bl/6 mice engineered to overexpress caveolin specifically in cardiac myocytes (Cav-3 OE), localization of caveolin to mitochondria increases membrane rigidity (4.2%; P<0.05), tolerance to calcium, and respiratory function (72% increase in state 3 and 23% increase in complex IV activity; P<0.05), while reducing stress-induced generation of reactive oxygen species (by 20% in cellular superoxide and 41 and 28% in mitochondrial superoxide under states 4 and 3, respectively; P<0.05) in Cav-3 OE vs. TGneg. By contrast, mitochondrial function is abnormal in caveolin-knockout mice and Caenorhabditis elegans with null mutations in caveolin (60% increase free radical in Cav-2 C. elegans mutants; P<0.05). In human colon cancer cells, mitochondria with increased caveolin have a 30% decrease in apoptotic stress (P<0.05), but cells with disrupted mitochondria-caveolin interaction have a 30% increase in stress response (P<0.05). Targeted gene transfer of caveolin to mitochondria in C57Bl/6 mice increases cardiac mitochondria tolerance to calcium, enhances respiratory function (increases of 90% state 4, 220% state 3, 88% complex IV activity; P<0.05), and decreases (by 33%) cardiac damage (P<0.05). Physical association and apparently the transfer of caveolin between caveolae and mitochondria is thus a conserved cellular response that confers protection from cellular damage in a variety of tissues and settings.
Scope The flavanol (-)-epicatechin (Epi), a component of cacao, has cardiac protective benefits in humans. Our previous study demonstrated Epi has δ-opioid receptor (DOR) binding activity and promotes cardiac protection. Here we examined the effects of 10 days of Epi treatment on: cardiac mitochondrial respiration, ROS production, calcium swelling, and mitochondrial membrane fluidity. Methods & Results Mice were randomized into four groups: (1) Control (Saline), (2) Naltrindole (Nalt; DOR antagonist), (3) Epi, and (4) Epi+Nalt and received 1 mg kg−1 Epi or water via oral gavage. Nalt groups received 5 mg kg−1 ip per day for 10 days. Significant increases in mitochondrial respiration and enhanced free radical production during state 3 respiration were observed with Epi. Additionally, we observed significant increases in rigidity of mitochondrial membranes and resistance to calcium induced mitochondrial swelling with Epi treatment. Blocking the DOR with Nalt resulted in decreases in all of the observed parameters by Epi treatment. Conclusion These findings indicate that Epi induces an integrated response that includes metabolic and structural changes in cardiac mitochondria resulting in greater functional capacity via DOR. Mitochondrial targeted effects of epicatechin may explain the physiologic benefit observed on cardiac protection and support epicatechin’s potential clinical application as a cardiac protective mimetic.
Diabetes is a worldwide epidemic with cardiovascular disease being a major complication. Caveolins act as scaffolding molecules for regulating signaling. Overexpression of caveolin protects the heart from cardiovascular stress. We hypothesize that cardiac‐specific caveolin‐3 (Cav‐3) overexpression (OE) will protect the diabetic heart. Transgene negative (TGneg) or Cav‐3 OE mice were given a single dose of streptozotocin (75mg/kg) and then placed on a high fat diet to induce type II diabetes mellitus (T2DM). After 3 months, TGneg T2DM mice and Cav‐3 OE T2DM mice showed an increase in body weight, altered glucose tolerance response, and increased insulin levels compared to controls on normal diet. Cav‐3 OE T2DM mitochondria showed protection from calcium swelling and reactive oxygen species generation similar to controls, when compared to TGneg T2DM mitochondria. Cav‐3 OE controls and Cav‐3OE T2DM showed increased protein expression of OPA‐1 and Mitofusin 2, compared to TGneg controls and TGneg T2DM. Mitochondrial ultrastructure (i.e., mitochondrial swelling and clustering) was preserved in Cav‐3 OE T2DM hearts compared to TGneg T2DM. Our data suggest that Cav‐3 OE in the heart has the ability to limit injury in the setting of diabetes through regulation of mitochondrial structure and function.
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