Lack of dystrophin is associated with altered integration of the mitochondria and ATPases in slow-twitch muscle cells of MDX mice

Braun U, Paju K, Eimre M, et al. Lack of dystrophin is associated with altered integration of the mitochondria and ATPases in slow-twitch muscle cells of MDX mice. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS. 2001;1505(2-3):258-270.The potential role of dystrophin-mediated control of systems integrating mitochondria with ATPases was assessed in muscle cells. Mitochondrial distribution and function in skinned cardiac and skeletal muscle fibers from dystrophin-deficient (MDX) and wild-type mice were compared. Laser confocal microscopy revealed disorganized mitochondrial arrays in m. gastrocnemius in MDX mice, whereas the other muscles appeared normal in this group. Irrespective of muscle type, the absence of dystrophin had no effect on the maximal capacity of oxidative phosphorylation, nor on coupling between oxidation and phosphorylation. However, in the myocardium and m. soleus, the coupling of mitochondrial creatine kinase to adenine nucleotide translocase was attenuated as evidenced by the decreased effect of creatine on the K-m for ADP in the reactions of oxidative phosphorylation. In m. soleus, a low K-m, for ADP compared to the wild-type counterpart was found, which implies increased permeability for that nucleotide across the mitochondrial outer membrane. In normal cardiac fibers 35% of the ADP flux generated by ATPases was not accessible to the external pyruvate kinase-phosphoenolpyruvate system, which suggests the compartmentalized (direct) channeling of that fraction of ADP to mitochondria. Compared to control, the direct ADP transfer was increased in MDX ventricles. In conclusion. our data indicate that in slow-twitch muscle cells, the absence of dystrophin is associated with the rearrangement of the intracellular energy and feedback signal transfer systems between mitochondria and ATPases. As the mechanisms mediated by creatine kinases become ineffective, the role of diffusion of adenine nucleotides increases due to the higher permeability of the mitochondrial outer membrane for ADP and enhanced compartmentalization of ADP flux. (C) 2001 Elsevier Science B.V. All rights reserved

IgG from patients with liver diseases inhibit mitochondrial respiration in permeabilized oxidative muscle cells: Impaired function of intracellular energetic units?

Kadaja L, Kisand KE, Peet N, et al. IgG from patients with liver diseases inhibit mitochondrial respiration in permeabilized oxidative muscle cells: Impaired function of intracellular energetic units? MOLECULAR AND CELLULAR BIOCHEMISTRY. 2004;256(1/2):291-303.The effect of IgG purified from the sera of healthy persons and patients with primary biliary cirrhosis (PBC) and chronic hepatitis ( CH) on ADP dependent respiration ( oxidative phosphorylation) in skinned muscle fibers from rat oxidative muscles ( heart and M. soleus) and glycolytic skeletal muscle ( M. gastrocnemius) was studied. The results show that IgG from three different sources inhibited the rate of respiration by 13, 44 and 42%, respectively, these effects being equally expressed in both types of oxidative muscles, whereas no inhibition was observed in glycolytic muscle. The following washout of unbound IgG did not abolish the inhibition of respiration suggesting that the specific interaction of IgG with antigens had taken place. Laser confocal analysis revealed binding of IgG predominantly to the sarcomeric structures such as Z-disk and M-lines in the cardiomyocytes. The staining of IgG within Z-disks and intermitochondrial space coincided throughout the muscle cells so that transversally serial spaces, each containing mitochondria and adjacent sarcomere, became clearly visible. When the IgG from a CH patient was incubated with the skinned myocardial fibers of the desmin knockout mice, its binding to Z-disks and the sarcomeric area was found to be similar to that in normal cardiac muscle. However, the transversal staining pattern was disintegrated, because of the slippage of the myofibrils in relation to each other and accumulation of mitochondria between them. These observations support the recent hypothesis that in oxidative muscles the mitochondria and adjacent sarcomeres form complexes, termed as the intracellular energetic units, ICEUs. Moreover, they indicate that human autoantibodies can be useful tools for localizing the proteins responsible for formation of ICEUs and modulation of their function. Thus, it appears that the proteins associated with the Z-disks and M-lines may participate in formation of ICEUs and that binding of IgG to these proteins decreases the access of exogenous adenine nucleotides to mitochondria, which manifests as decreased rate of ADP-dependent respiration