TY - JOUR
T1 - Defects in calcium homeostasis and mitochondria can be reversed in Pompe disease
AU - Lim, Jeong A.
AU - Li, Lishu
AU - Kakhlon, Or
AU - Myerowitz, Rachel
AU - Raben, Nina
N1 - Publisher Copyright:
© 2015 Taylor & Francis Group, LLC.
PY - 2015
Y1 - 2015
N2 - 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 Ca2+ homeostasis, mitochondrial Ca2+ 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 Ca2+ channel in Pompe muscle cells. This study provides strong evidence that disturbance of Ca2+ 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 Ca2+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.
AB - 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 Ca2+ homeostasis, mitochondrial Ca2+ 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 Ca2+ channel in Pompe muscle cells. This study provides strong evidence that disturbance of Ca2+ 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 Ca2+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.
KW - Autophagy
KW - Calcium
KW - Lysosome
KW - Mitochondria
KW - Mitophagy
KW - Pompe disease
UR - http://www.scopus.com/inward/record.url?scp=84948825234&partnerID=8YFLogxK
U2 - 10.1080/15548627.2015.1009779
DO - 10.1080/15548627.2015.1009779
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C2 - 25758767
AN - SCOPUS:84948825234
SN - 1554-8627
VL - 11
SP - 385
EP - 402
JO - Autophagy
JF - Autophagy
IS - 2
ER -