title: Defects in calcium homeostasis and mitochondria can be reversed in Pompe disease.
abstract: Mitochondria-induced oxidative stress and flawed autophagy are common features of neurodegenerative and lysosomal storage diseases (LSDs). Although defective autophagy is particularly prominent in Pompe disease, mitochondrial function has escaped examination in this typical LSD. We have found multiple mitochondrial defects in mouse and human models of Pompe disease, a life-threatening cardiac and skeletal muscle myopathy: a profound dysregulation of Ca(2+) homeostasis, mitochondrial Ca(2+) overload, an increase in reactive oxygen species, a decrease in mitochondrial membrane potential, an increase in caspase-independent apoptosis, as well as a decreased oxygen consumption and ATP production of mitochondria. In addition, gene expression studies revealed a striking upregulation of the β 1 subunit of L-type Ca(2+) channel in Pompe muscle cells. This study provides strong evidence that disturbance of Ca(2+) homeostasis and mitochondrial abnormalities in Pompe disease represent early changes in a complex pathogenetic cascade leading from a deficiency of a single lysosomal enzyme to severe and hard-to-treat autophagic myopathy. Remarkably, L-type Ca(2+)channel blockers, commonly used to treat other maladies, reversed these defects, indicating that a similar approach can be beneficial to the plethora of lysosomal and neurodegenerative disorders.
authors.affiliation: a Laboratory of Muscle Stem Cells and Gene Regulation; National Institute of Arthritis and Musculoskeletal and Skin Diseases ; National Institutes of Health; Bethesda ; MD USA.
authors.forename: Jeong-A
authors.initials: JA
authors.lastname: Lim
authors.forename: Lishu
authors.initials: L
authors.lastname: Li
authors.forename: Or
authors.initials: O
authors.lastname: Kakhlon
authors.forename: Rachel
authors.initials: R
authors.lastname: Myerowitz
authors.forename: Nina
authors.initials: N
authors.lastname: Raben
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D002118:Calcium / Q000172:deficiency*; D006009:Glycogen Storage Disease Type II / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D000520:alpha-Glucosidases / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D000520:alpha-Glucosidases; D002118:Calcium
keywords: AIFM1, apoptosis-inducing factor, mitochondrion-associated, 1; CCCP, carbonyl cyanide m-chlorophenylhydrazone; DMEM, Dulbecco's modified Eagle's medium; EGTA, ethylene glycol-bis(2-aminoethylether)-N, N, N′, N′-tetraacetic acid; ERT, enzyme replacement therapy; GAA, glucosidase; GFP, green fluorescent protein; LAMP1, lysosomal-associated membrane protein 1; LSD, lysosomal storage disease; MAP1LC3A/B (LC3), microtubule-associated protein 1 light chain 3 α/β; MOPS, 3-morpholinopropane-1-sulfonic acid; MitoG, MitoTracker Green; OMM, outer mitochondrial membrane; Pompe disease; RFP, red fluorescent protein; ROS, reactive oxygen species; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; Ub, ubiquitinated; VDCC, voltage-dependent Ca2+ channel; autophagy; calcium; lysosome; mitochondria; mitophagy; α, acid