Defects in calcium homeostasis and mitochondria can be reversed in Pompe disease

Autophagy
Jeong-A LimNina Raben

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, i...Continue Reading

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Datasets Mentioned

BETA
GSE57980

Methods Mentioned

BETA
biopsies
confocal microscopy
ubiquitination
FACS
electron
biopsy
Assay
Protein Assay
Illumina sequencing
PCA

Software Mentioned

ImageJ
Image J
TopHat
CASAVA
DAVID
Partek Genomics Suite

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