Involvement of Mitochondrial Disorders in Septic Cardiomyopathy

Figure 2

Mitochondrial disorders in septic cardiomyopathy. Increased reactive oxygen species (ROS) and nitric oxide (NO) production may cause direct oxidative or nitrosative damage and inhibition of oxidative phosphorylation (OXPHOS) complexes, leading to decreased O₂ consumption and proton-motive force between the intermembrane space and the matrix (∆p). Reduced calcium (Ca²⁺) uptake by and increased Ca²⁺ leakage from the sarcoplasmic reticulum result in cytosolic and mitochondrial Ca²⁺ overload. Increased ROS/NO production, along with Ca²⁺ overload trigger the opening of the mitochondrial permeability transition pore (mPTP). This results in mitochondrial uncoupling of adenosine triphosphate (ATP) synthesis from O₂ consumption (i.e., OXPHOS uncoupling) and a decreased ∆p. Altered mitochondrial cyclic adenosine monophosphate (cAMP) protein kinase A (PKA) signaling also promotes OXPHOS uncoupling and decreased ∆p. Decreased ∆p leads to ATP synthase (FOF1) inhibition and energy deficit. The mPTP opening and other mechanisms, as yet poorly described, induce externalization of mitochondrial components to the cytosol and the extracellular space that activates the inflammation pathway. Decreased ∆p, the presence of oxidized proteins, and externalization of mitochondrial components in the cytosol activate intrinsic apoptosis, leading to reduction in myofilament response to Ca²⁺. Although ∆p and the presence of oxidized proteins activate auto-mitophagy, RhoA-ROCK activation results in automitophagy failure. As increased ROS production, cytosolic Ca²⁺ overload and energy deficit activate mitochondrial biogenesis, and peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1 alpha) disorders result in mitochondrial biogenesis failure. Overall, increased inflammation, energy deficit, reduced myofilament response to Ca²⁺, impaired automitophagy, and failure in mitochondrial biogenesis are the features of mitochondrial disorders in septic cardiomyopathy. ADP: adenosine diphosphate; CI, CII, CIII, and CIV: the four complexes in the mitochondrial respiratory chain; mtDNA: mitochondrial DNA; RYR: ryanodine receptor; SERCA: sarcoendoplasmic reticulum Ca²⁺ pump.