Mitochondrial dysfunction in heart failure affects interfibrillar but not subsarcolemmal mitochondria

Objectives: Pressure overload induced heart failure is correlated with significant impairment in mitochondrial function. In normoxia >95% of the ATP is produced there. In heart muscle, two types of mitochondria exist. Subsarcolemmal mitochondria (SSM), presumably providing ATP for basic cell function, and interfibrillar mitochondria (IFM), presumably providing energy for the contractile apparatus. We speculated that the respiratory capacities of these subpopulations are differentially affected by pressure overload.

Methods: Male Sprague-Dawley rats were subjected to transverse aortic constriction (TAC) for 20 weeks. Contractile function was assessed by echocardiography. Mitochondria were isolated by differential centrifugation and respiratory capacity was analyzed using a Clark electrode.

Results: Left ventricular posterior wall diameter was increased (LVPWD: 2.6±0.2 vs. 1.4±0.2mm; p<0.05) after 10 weeks and TAC resulted in reduced EF (53±8 vs. 75±6%; p<0.05) after 20 weeks, indicating heart failure. The mitochondrial marker enzyme, citrate synthase, was significantly reduced in heart failure (U/100mg tissue: 15.3±2.0 vs. 24.6±2.1). State 3 respiration of isolated SSM was unchanged with all substrates. In contrast respiratory capacity of IFM was impaired with complex-I substrates (natomsO/min/mg protein: glutamate 239±64 vs. 503±91, palmitoyl-carnitine 241±27 vs. 521±83 and pyruvate 198±14 vs. 615±107; p<0.05) but unchanged with succinate as complex-II substrate.

Conclusion: Contractile dysfunction in heart failure is associated with significant impairment of mitochondrial respiratory capacity. However, this effect is limited to the interfibrillar mitochondria. The selective impairment in respiratory capacity of IFM supports the notion of IFMs main role in producing ATP for contractile function.