Mitochondrial @entity460 overload is a key determinant in XXXX .

@entity671 @entity712 @entity66 @entity19 @entity26 @entity8452 @entity63120 @entity1188 @entity460 @entity23395 @entity141 @entity855
@entity460 ( @entity141 ) released from the sarcoplasmic reticulum (SR) is crucial for excitation-contraction (E-C) coupling. Mitochondria, the major source of energy, in the form of @entity855 , required for cardiac contractility, are closely interconnected with the SR, and @entity141 is essential for optimal function of these organelles. However, @entity141 accumulation can impair mitochondrial function, leading to reduced @entity855 production and increased release of reactive @entity26 species (ROS). @entity66 contributes to @entity712 ( @entity712 ), but whether mitochondrial @entity141 plays a mechanistic role in @entity712 remains unresolved. Here, we show for the first time, to our knowledge, that diastolic SR @entity141 leak causes mitochondrial @entity141 overload and dysfunction in a @entity19 model of @entity1188 @entity712 . There are two forms of @entity141 release channels on cardiac SR: type 2 @entity8452 receptors ( @entity23395 s) and type 2 @entity671 receptors (IP3R2s). Using @entity19 models harboring @entity23395 mutations that either cause or inhibit SR @entity141 leak, we found that leaky @entity23395 channels result in mitochondrial @entity141 overload, dysmorphology, and malfunction. In contrast, cardiac-specific deletion of @entity63120 had no major effect on mitochondrial fitness in @entity712 . Moreover, genetic enhancement of mitochondrial antioxidant activity improved mitochondrial function and reduced posttranslational modifications of @entity23395 macromolecular complex. Our data demonstrate that leaky @entity23395 , but not @entity63120 , channels cause mitochondrial @entity141 overload and dysfunction in @entity712 .
