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MITOCHONDRIAL PLASTICITY IN SKELETAL MUSCLE CELLS New evidence on mitochondria mtDNA Morpho-functional changes MITO TRACKER GREEN Mito Tracker Green is a mitochondrial-selective fluorescent label Mitochondria are dynamic organelles Mitochondria fuse and divide to form constantly changing tubular networks in most eukaryotic cells (A) Mitochondrial network (green) in a Saccharomyces cerevisiae cell. (B) Mammalian mitochondrial network in a fibroblast cells. Hales, K. G. (2010) Mitochondrial network in skeletal muscle cells C D Confocal microscopy of myoblasts (A, B) and late myotubes (C,D,E) after Mito Tracker staining Barbieri et al., 2011 Bar=20μm The mitochondrium is active when the mitochondrial membrane potential (MMP) is highly negative ΔΨ ~ -180mV across the inner membrane of mitochondria The electron transport system (ETS) pumps protons across the inner mitochondrial membrane (i.m) and thus generates mitochondrial membrane potential (MMP). The MMP is necessary for conversion of ADP to ATP (ATP synthesis). When is a mitochondrium active? When the membrane potential (MMP) is highly negative When it produces ATP When it breathes Mitchondria are in a constant state of fusion and division inside the cell Mouli et al., Frequency and selectivity of mitochondrial fusion are key to its quality maintenance function, Biophysical Journal (2009) BALANCE OF MITOCHONDRIAL FUSION AND FISSION 1 um BALANCE OF MITOCHONDRIAL FUSION AND DIVISION Three central players belong to the dynamin superfamily : (1) mitofusins (outer mitochondrial membrane fusion), (2) OPA1/Mgm1 (inner mitochondrial membrane fusion), (3) Drp1/Dnm1 (division of outer and inner mitochondrial membranes). MITOCHONDRIAL ARRANGEMENT IN MUSCLE CELLS A B C Representative confocal images of : (A) Cardiomyocites; (B) soleus fibers; (C) white gastrocnemius fibers. Vendelin et al., Am J Physiol Cell Physiol 288: C757–C767, 2005 MITOCHONDRIAL ARRANGEMENT IN MUSCLE CELLS Birkedal, R. et al. Am J Physiol Cell Physiol 291: C1148-C1158 2006 MITOCHONDRIAL POPULATIONS IN MUSCLE CELLS Recent studies have shown multiple functional interactions among mitochondria, sarcoplasmic reticulum and myofibrilles in skeletal muscle fiber sarcomere myofibrilles Sarcoplasmic membrane sarcoplasmic reticulum mitochondria SS Transmission electron micrograph of SS subsarcolemmar and IMF intramyofibrillar mitochondria IMF in muscle fiber Kindly provided by Hood D, 2004 Anderson et al. 1981 Nature 290, 457 - 465 “The complete sequence of the 16,569base pair human mitochondrial genome (mtDNA) is presented…” Human mitochondrial genome (mtDNA) mtDNA : 16,569 base pairs MITOMAP (http://www.mitomap.org/MITOMAP) 37 genes: 2 rRNA; 22 tRNA; 13 mRNA for oxidative enzimatic subunits MITOCHONDRIAL MYOPATHIES Leber's hereditary optic neuropathy (LHON) visual loss , progressive degeneration of the optic nerves and retina Leigh syndrome, sclerosing encephalopathy Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP) Myoclonic Epilepsy with Ragged Red Fibers (MERRF) progressive epilepsy, "Ragged Red Fibers" – clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fiber and appear as "Ragged Red Fibers”, short stature, hearing loss Mitochondrial myopathy, encephalomyopathy, acidosis, stroke-like symptoms (MELAS) NUCLEAR AND MITOCHONDRIAL DNA COOPERATION Nucleus or mitochondria Mitochondria Nucleus Most mitochondrial components are encoded by the nuclear genome (blue); The components in pink are encoded by mtDNA in some eukaryotes but by the nuclear genome in other eukaryotes; while a small portion is specified by mtDNA (orange). Burger et al. 2003 NUCLEAR AND MITOCHONDRIAL DNA COOPERATION Complex Mitochondrial genes I NADH dehydrogenase II Succinate CoQ Reductase III Cytochrome b-c1 IV Cyctochrome c-oxidase V ATP synthase 7 0 1 3 1 Nuclear genes > 25 4 10 10 11 MITOCHONDRIAL FUNCTIONS Maintenance of energy stores, ergogenics Thermogenesis Apoptosis Pathological processes associated with mtDNA mutations (MELAS MERRF NARP), APOPTOSIS Apoptosis, or programmed cell death, is a normal component of the development and health of multicellular organisms. The breakdown of chromatin in the nucleus The end stages of apoptosis are characterised by membrane blebs. Small vesicles called apoptotic bodies are also sometimes observed (D, arrow). APOPTOSIS FUNDAMENTALS OF MUSCLE MITOCHONDRIAL BIOGENESIS AdipoR1, adiponectin receptor 1; AMPK, AMP-activated protein kinase; AS160, Akt substrate of 160 kDa; GLUT4, glucose transporter 4; IMTG, intramyocellular triglyceride; IRS, insulin receptor substrate; LAT1, L-type amino acid transporter; mTOR, mammalian target of rapamycin; ROS, reactive oxygen species; SIRT1, sirtuin 1; PGC-1, peroxisome proliferator-activated receptor-γ coactivator-1; PPAR, peroxisome proliferator-activated receptor. (Hawley et al., 2010) FUNDAMENTALS OF MUSCLE MITOCHONDRIAL BIOGENESIS Six weeks of resistance training increases skeletal muscle mitochondrial content between ___% and ____% NYC Marathon